1′substituted carba-nucleoside analogs for antiviral treatment

ABSTRACT

Provided are pyrrolo[1,2-f][1,2,4]triazinyl, imidazo[1,5-f][1,2,4]triazinyl, imidazo[1,2-f][1,2,4]triazinyl, and [1,2,4]triazolo[4,3-f][1,2,4]triazinyl nucleosides, nucleoside phosphates and prodrugs thereof, wherein the 1′ position of the nucleoside sugar is substituted with a cyano group. The compounds, compositions, and methods provided are useful for the treatment of Flaviviridae virus infections, particularly hepatitis C infections.

This application is a continuation of U.S. application Ser. No.12/428,176, filed Apr. 22, 2009, now U.S. Pat. No. 8,008,265, whichclaims benefit of U.S. provisional Applications 61/047,263 filed Apr.23, 2008 and 61/139,449 filed Dec. 19, 2008 both of which are hereinincorporated by reference in their entireties for all purposes.

FIELD OF THE INVENTION

The invention relates generally to compounds with antiviral activity,more particularly nucleosides active against Flaviviridae infections andmost particularly to inhibitors of hepatitis C virus RNA-dependent RNApolymerase.

BACKGROUND OF THE INVENTION

Viruses comprising the Flaviviridae family comprise at least threedistinguishable genera including pestiviruses, flaviviruses, andhepaciviruses (Calisher, et al., J. Gen. Virol., 1993, 70, 37-43). Whilepestiviruses cause many economically important animal diseases such asbovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV,hog cholera) and border disease of sheep (BDV), their importance inhuman disease is less well characterized (Moennig, V., et al., Adv. Vir.Res. 1992, 48, 53-98). Flaviviruses are responsible for important humandiseases such as dengue fever and yellow fever while hepaciviruses causehepatitis C virus infections in humans. Other important viral infectionscaused by the Flaviviridae family include West Nile virus (WNV)Janpanese encephalitis virus (JEV), tick-borne encephalitis virus,Junjin virus, Murray Valley encephalitis, St Louis enchaplitis, Omskhemorrhagic fever virus and Zika virus. Combined, infections from theFlaviviridae virus family cause significant mortality, morbidity andeconomic losses throughout the world. Therefore, there is a need todevelop effective treatments for Flaviviridae virus infections.

The hepatitis C virus (HCV) is the leading cause of chronic liverdisease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) so asignificant focus of current antiviral research is directed toward thedevelopment of improved methods of treatment of chronic HCV infectionsin humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American,October: 80-85, (1999); Gordon, C. P., et al., J. Med. Chem. 2005, 48,1-20; Maradpour, D.; et al., Nat. Rev. Micro. 2007, 5(6), 453-463). Anumber of HCV treatments are reviewed by Bymock et al. in AntiviralChemistry & Chemotherapy, 11:2; 79-95 (2000).

RNA-dependent RNA polymerase (RdRp) is one of the best studied targetsfor the development of novel HCV therapeutic agents. The NS5B polymeraseis a target for inhibitors in early human clinical trials (Sommadossi,J., WO 01/90121 A2, US 2004/0006002 A1). These enzymes have beenextensively characterized at the biochemical and structural level, withscreening assays for identifying selective inhibitors (De Clercq, E.(2001) J. Pharmacol. Exp. Ther. 297:1-10; De Clercq, E. (2001) J. Clin.Virol. 22:73-89). Biochemical targets such as NS5B are important indeveloping HCV therapies since HCV does not replicate in the laboratoryand there are difficulties in developing cell-based assays andpreclinical animal systems.

Currently, there are primarily two antiviral compounds, ribavirin, anucleoside analog, and interferon-alpha (α) (IFN), which are used forthe treatment of chronic HCV infections in humans. Ribavirin alone isnot effective in reducing viral RNA levels, has significant toxicity,and is known to induce anemia. The combination of IFN and ribavirin hasbeen reported to be effective in the management of chronic hepatitis C(Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half thepatients given this treatment show a persistent benefit. Other patentapplications disclosing the use of nucleoside analogs to treat hepatitisC virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO02/032920, WO 02/18404, WO 04/046331, WO2008/089105 and WO2008/141079but additional treatments for HCV infections have not yet becomeavailable for patients. Therefore, drugs having improved antiviral andpharmacokinetic properties with enhanced activity against development ofHCV resistance, improved oral bioavailability, greater efficacy, fewerundesirable side effects and extended effective half-life in vivo (DeFrancesco, R. et al. (2003) Antiviral Research 58:1-16) are urgentlyneeded.

Certain ribosides of the nucleobases pyrrolo[1,2-f][1,2,4]triazine,imidazo[1,5-f][1,2,4]triazine, imidazo[1,2-f][1,2,4]triazine, and[1,2,4]triazolo[4,3-f][1,2,4]triazine have been disclosed inCarbohydrate Research 2001, 331(1), 77-82; Nucleosides & Nucleotides(1996), 15(1-3), 793-807; Tetrahedron Letters (1994), 35(30), 5339-42;Heterocycles (1992), 34(3), 569-74; J. Chem. Soc. Perkin Trans. 1 1985,3, 621-30; J. Chem. Soc. Perkin Trans. 1 1984, 2, 229-38; WO 2000056734;Organic Letters (2001), 3(6), 839-842; J. Chem. Soc. Perkin Trans. 11999, 20, 2929-2936; and J. Med. Chem. 1986, 29(11), 2231-5. However,these compounds have not been disclosed as useful for the treatment ofHCV. Babu, Y. S., WO2008/089105 and WO2008/141079, discloses ribosidesof pyrrolo[1,2-f][1,2,4]triazine nucleobases with antiviral, anti-HCV,and anti-RdRp activity.

SUMMARY OF THE INVENTION

The instant invention provides compounds that inhibit viruses of theFlaviviridae family. The invention also comprises compounds that inhibitviral nucleic acid polymerases, particularly HCV RNA-dependent RNApolymerase (RdRp), rather than cellular nucleic acid polymerases.Therefore, the compounds of the instant invention are useful fortreating Flaviviridae infections in humans and other animals.

In one aspect, this invention provides a compound of Formula I:

or a pharmaceutically acceptable salt, thereof;

wherein:

each R¹, R², R³, R⁴, or R⁵ is independently H, OR^(a), N(R^(a))₂, N₃,CN, NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl,(C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, or aryl(C₁-C₈)alkyl;

or any two R¹, R², R³, R⁴, or R⁵ on adjacent carbon atoms when takentogether are —O(CO)O— or when taken together with the ring carbon atomsto which they are attached form a double bond;

R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂, S(O)_(n)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl,(C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substitutedalkynyl, or aryl(C₁-C₈)alkyl or R⁶ and either R¹ or R² when takentogether are —O(CO)O—;

each n is independently 0, 1, or 2;

each R^(a) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), or —SO₂NR¹¹R¹²;

R⁷ is H, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², or

each Y or Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), orN—NR₂;

W¹ and W², when taken together, are —Y³(C(R^(y))₂)₃Y³—; or one of W¹ orW² together with either R³ or R⁴ is —Y³— and the other of W¹ or W² isFormula Ia; or W¹ and W² are each, independently, a group of the FormulaIa:

wherein:

each Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),N—NR₂, S, S—S, S(O), or S(O)₂;

each Y³ is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^(x) is independently R^(y) or the formula:

wherein:

each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR,—N(R)C(═Y¹)N(R)₂, —SO₂NR₂, —CN, —N₃, —NO₂, —OR, or W³; or when takentogether, two R^(y) on the same carbon atom form a carbocyclic ring of 3to 7 carbon atoms;

each R is independently H, (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈)substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ substituted heterocyclyl, arylalkyl or substitutedarylalkyl;

W³ is W⁴ or W⁵; W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or —SO₂W⁵;and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independentlysubstituted with 0 to 3 R^(y) groups;

each X¹ or X² is independently C—R¹⁰ or N;

each R⁸ is halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO,CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹, R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or aryl(C₁-C₈)alkyl; or R¹¹ and R¹² taken togetherwith a nitrogen to which they are both attached form a 3 to 7 memberedheterocyclic ring wherein any one carbon atom of said heterocyclic ringcan optionally be replaced with —O—, —S— or —NR^(a)—;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl of each R¹, R², R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is,independently, optionally substituted with one or more halo, hydroxy,CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more of the non-terminalcarbon atoms of each said (C₁-C₈)alkyl may be optionally replaced with—O—, —S— or —NR^(a)—.

In another aspect, the present invention includes compounds of Formula Iand pharmaceutically acceptable salts thereof and all racemates,enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs andamorphous forms thereof.

In another aspect, the present invention provides novel compounds ofFormula I with activity against infectious Flaviviridae viruses. Withoutwishing to be bound by theory, the compounds of the invention mayinhibit viral RNA-dependent RNA polymerase and thus inhibit thereplication of the virus. They are useful for treating human patientsinfected with a human virus such as hepatitis C.

In another aspect, the invention provides a pharmaceutical compositioncomprising an effective amount of a Formula I compound, or apharmaceutically acceptable salt thereof, in combination with apharmaceutically acceptable diluent or carrier.

In another embodiment, the present application provides for combinationpharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of FormulaI; or a pharmaceutically acceptable salt, solvate, or ester thereof; and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent selected from the group consisting ofinterferons, ribavirin analogs, NS3 protease inhibitors, NS5ainhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors,hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs fortreating HCV.

In another embodiment, the present application provides for a method ofinhibiting HCV polymerase, comprising contacting a cell infected withHCV with an effective amount of a compound of Formula I; or apharmaceutically acceptable salts, solvate, and/or ester thereof.

In another embodiment, the present application provides for a method ofinhibiting HCV polymerase, comprising contacting a cell infected withHCV with an effective amount of a compound of Formula I; or apharmaceutically acceptable salts, solvate, and/or ester thereof; and atleast one additional therapeutic agent.

In another embodiment, the present application provides for a method oftreating and/or preventing a disease caused by a viral infection whereinthe viral infection is caused by a virus selected from the groupconsisting of dengue virus, yellow fever virus, West Nile virus,Japanese encephalitis virus, tick-borne encephalitis virus, Junjinvirus, Murray Valley encephalitis virus, St Louis encephalitis virus,Omsk hemorrhagic fever virus, bovine viral disarrhea virus, Zika virusand Hepatitis C virus; by administering to a subject in need thereof atherapeutically effective amount of a compound of Formula I, or apharmaceutically acceptable salt thereof.

In another embodiment, the present application provides for a method oftreating HCV in a patient, comprising administering to said patient atherapeutically effective amount of a compound of Formula I; or apharmaceutically acceptable salt, solvate, and/or ester thereof.

In another embodiment, the present application provides for a method oftreating HCV in a patient, comprising administering to said patient atherapeutically effective amount of a compound of Formula I; or apharmaceutically acceptable salt, solvate, and/or ester thereof; and atleast one additional therapeutic agent.

Another aspect of the invention provides a method for the treatment orprevention of the symptoms or effects of an HCV infection in an infectedanimal which comprises administering to, i.e. treating, said animal witha pharmaceutical combination composition or formulation comprising aneffective amount of a Formula I compound, and a second compound havinganti-HCV properties.

In another aspect, the invention also provides a method of inhibitingHCV, comprising administering to a mammal infected with HCV an amount ofa Formula I compound, effective to inhibit the replication of HCV ininfected cells in said mammal.

In another aspect, the invention also provides processes and novelintermediates disclosed herein which are useful for preparing Formula Icompounds of the invention.

In other aspects, novel methods for synthesis, analysis, separation,isolation, purification, characterization, and testing of the compoundsof this invention are provided.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingdescription, structures and formulas. While the invention will bedescribed in conjunction with the enumerated embodiments, it will beunderstood that they are not intended to limit the invention to thoseembodiments. On the contrary, the invention is intended to cover allalternatives, modifications, and equivalents, which may be includedwithin the scope of the present invention.

In another aspect, compounds of Formula I are represented by Formula II:

or a pharmaceutically acceptable salt, thereof;

wherein:

each R¹, R², R³, R⁴, or R⁵ is independently H, OR^(a), N(R^(a))₂, N₃,CN, NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl,(C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, or aryl(C₁-C₈)alkyl;

or any two R¹, R², R³, R⁴, or R⁵ on adjacent carbon atoms when takentogether are —O(CO)O— or when taken together with the ring carbon atomsto which they are attached form a double bond;

R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂, S(O)_(n)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl,(C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substitutedalkynyl, or aryl(C₁-C₈)alkyl or R⁶ and either R¹ or R² when takentogether are —O(CO)O—;

each n is independently 0, 1, or 2;

each R^(a) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹—,—S(O)(OR¹¹), —S(O)₂(OR¹¹), or —SO₂NR¹¹R¹²;

R⁷ is H, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹,—S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², or

each Y or Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), orN—NR₂;

W¹ and W², when taken together, are —Y³(C(R^(y))₂)₃Y³—; or one of W¹ orW² together with either R³ or R⁴ is —Y³— and the other of W¹ or W² isFormula Ia; or W¹ and W² are each, independently, a group of the FormulaIa:

wherein:

each Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),N—NR₂, S, S—S, S(O), or S(O)₂;

each Y³ is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^(x) is independently R^(y) or the formula:

wherein:

each M1a, M1c, and M1d is independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR,—N(R)C(═Y¹)N(R)₂, —SO₂NR₂, —CN, —N₃, —NO₂, —OR, or W³; or when takentogether, two R^(y) on the same carbon atom form a carbocyclic ring of 3to 7 carbon atoms;

each R is independently H, (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈)substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ substituted heterocyclyl, arylalkyl or substitutedarylalkyl;

W³ is W⁴ or W⁵; W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or —SO₂W⁵;and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independentlysubstituted with 0 to 3 R^(y) groups;

X² is C—R¹⁰ and each X¹ is independently C—R¹⁰ or N;

each R⁸ is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃,NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹;

each R⁹ or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹),—CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, optionally substituted aryl,optionally substituted heteroaryl, —C(═O)(C₁-C₈)alkyl,—S(O)_(n)(C₁-C₈)alkyl or aryl(C₁-C₈)alkyl; or R¹¹ and R¹² taken togetherwith a nitrogen to which they are both attached form a 3 to 7 memberedheterocyclic ring wherein any one carbon atom of said heterocyclic ringcan optionally be replaced with —O—, —S— or —NR^(a)—;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl of each R¹, R², R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is,independently, optionally substituted with one or more halo, hydroxy,CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more of the non-terminalcarbon atoms of each said (C₁-C₈)alkyl may be optionally replaced with—O—, —S— or —NR^(a)—.

In one embodiment of the invention of Formula II, R¹ is (C₁-C₈)alkyl,(C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment,R¹ is (C₁-C₈)alkyl. In another aspect of this embodiment, R¹ is methyl,CH₂OH, CH₂F, ethenyl, or ethynyl. In a preferred aspect of thisembodiment, R¹ is methyl. In another preferred aspect of thisembodiment, R¹ is H.

In one embodiment of Formula II, R² is H, OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or (C₂-C₈)substituted alkynyl. In another aspect of this embodiment, R² is H,OR^(a), N(R^(a))₂, N₃, CN, SR^(a) or halogen. In another aspect of thisembodiment, R² is H, OH, NH₂, N₃, CN, or halogen. In another aspect ofthis embodiment, R² is OR^(a) or halogen and R¹ is H, (C₁-C₈)alkyl,(C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment,R² is OR^(a) or F and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl.In a preferred aspect of this embodiment, R² is OH and R¹ is H, methyl,CH₂OH, CH₂F, ethenyl, or ethynyl. In another preferred aspect of thisembodiment, R² is OR^(a) and R¹ is H. In another preferred aspect ofthis embodiment, R² is OH and R¹ is H. In another preferred aspect ofthis embodiment, R² is F and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, orethynyl. In another preferred aspect of this embodiment, R² is OR^(a)and R¹ is methyl. In a particularly preferred aspect of this embodiment,R² is OH and R¹ is methyl.

In one embodiment of Formula II, R³ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In oneaspect of this embodiment, R³ is H or F. In a preferred aspect of thisembodiment, R³ is H. In another preferred aspect of this embodiment, R³is H, R² is OR^(a) or halogen and R¹ is H, (C₁-C₈)alkyl, (C₂-C₈) alkenylor (C₂-C₈)alkynyl. In another aspect of this embodiment, R³ is H, R² isOR^(a) or F and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl. Inanother aspect of this embodiment, R³ is H, R² is OR^(a) and R¹ ismethyl. In another aspect of this embodiment, R³ is H, R² is OH and R¹is methyl. In another aspect of this embodiment, R³ is H, R² is OR^(a)or F and R¹ is H. In another aspect of this embodiment, R³ is H, R² isOH and R¹ is H. In another aspect of this embodiment, each R¹, R³ and R⁵is H and R² is OH.

In one embodiment of Formula II, R⁴ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In apreferred aspect of this embodiment, R⁴ is OR^(a). In another preferredaspect of this embodiment, R⁴ is OR^(a), R² is OR^(a) or halogen and R¹is H, (C₁-C₈)alkyl, (C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In anotherpreferred aspect of this embodiment, R⁴ is OR^(a), R² is OR^(a) orhalogen and R¹ is H. In another preferred aspect of this embodiment, R⁴is OR^(a), R² is OR^(a) or halogen, R³ is H and R¹ is H, (C₁-C₈)alkyl,(C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In another preferred embodiment R⁴ isOR^(a), R² is OR^(a) or F and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, orethynyl. In another preferred aspect of this embodiment, R⁴ is OR^(a),R² is OR^(a) or F, R³ is H and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, orethynyl. In another preferred aspect of this embodiment, R⁴ and R² are,independently, OR^(a) and R¹ is methyl. In another preferred aspect ofthis embodiment, R⁴ and R² are, independently OR^(a), R³ is H and R¹ ismethyl. In another preferred aspect of this embodiment, R⁴ and R², takentogether, are —O(CO)O—, R³ is H and R¹ is methyl. In another preferredaspect of this embodiment, one of R⁴ or R² is OR^(a) and the other of R⁴or R² is OH. In another preferred aspect of this embodiment, one of R⁴or R² is OR^(a) wherein R^(a) is not H and the other of R⁴ or R² is OH,R³ is H, and R¹ is methyl. In another preferred aspect of thisembodiment, R⁴ and R² are OH, R³ is H, and R¹ is methyl. In anotherpreferred aspect of this embodiment, R⁴ is OR^(a), R² is OR^(a) or F,and each R¹ and R³ is H. In another preferred aspect of this embodiment,R⁴ and R² are, independently, OR^(a) and R¹ is H. In another preferredaspect of this embodiment, R⁴ and R² are, independently OR^(a) and eachR¹ and R³ is H. In another preferred aspect of this embodiment, R⁴ andR², taken together, are —O(CO)O—, and each R¹ and R³ is H.

In one embodiment of Formula II, R⁵ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. Inanother aspect of this embodiment, R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂,S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl. In another aspect of thisembodiment, R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl,(C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substitutedalkynyl, or aryl(C₁-C₈)alkyl and R⁵ is H, N₃, CN, (C₁-C₈)alkyl,(C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment,R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or (C₂-C₈)substituted alkynyl; R⁵ is H, N₃, CN, methyl, ethenyl or ethynyl; R⁴ isOR^(a) and R³ is H. In another aspect of this embodiment, R⁶ is OR^(a),N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R⁵ is H or N₃, R⁴ is OR^(a), R³ is H, and R² is For OR^(a). In another aspect of this embodiment, R⁶ is OR^(a), N₃, CN,S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R⁵ is H or N₃, R⁴ is OR^(a), R³ is H, R² is OR^(a)and R¹ is methyl, CH₂OH, CH₂F, ethenyl, or ethynyl. In another aspect ofthis embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl, R³ and R⁵ are H,R² and R⁴ are, independently, OR^(a), and R¹ is methyl. In anotheraspect of this embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl, each R¹,R³ and R⁵ is H, and R² and R⁴ are, independently, OR^(a). In anotheraspect of this embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl, R³ and R⁵are H, R² and R⁴ are OH, and R¹ is methyl. In another aspect of thisembodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl, R¹, R³ and R⁵ areeach H and R² and R⁴ are OH. In another aspect of this embodiment, R⁶ isOR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R³ and R⁵ are H, R² and R⁴, taken together, are—O(CO)O—, and R¹ is methyl. In another aspect of this embodiment, R⁶ isOR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R¹, R³ and R⁵ are each H and R² and R⁴, takentogether, are —O(CO)O—. In another aspect of this embodiment, R⁶ isOR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R¹ and R³ are each H, R² and R⁴ are independentlyOR^(a) and R⁵ is N₃.

In one embodiment of Formula II, R² and R⁴ are each OR^(a) and at leastone of R¹, R³, or R⁵ is not H. In another aspect of this embodiment, R²and R⁴ are each OR^(a) and R¹ is (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. In another embodiment,R² and R⁴ are each OR^(a) and R³ is (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. In another aspect ofthis embodiment, R² and R⁴ are each OR^(a) and R⁵ is OR^(a), N(R^(a))₂,N₃, CN, NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. In another aspect ofthis embodiment, R² and R⁴ are each OR^(a) and R⁶ is OR^(a), N(R^(a))₂,N₃, CN, NO₂, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, (C₁-C₈)alkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynylor aryl(C₁-C₈)alkyl. In another aspect of this embodiment, R² and R⁴ areboth OH and R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or(C₂-C₈) substituted alkynyl.

In another embodiment of Formula II, each R¹ and R² is H, one of R³ orR⁴ is OR^(a) and the other of R³ or R⁴ is (C₁-C₈)alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. Inanother aspect of this embodiment, each R¹ and R² is H, one of R³ or R⁴is OH and the other of R³ or R⁴ is (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl.

In another embodiment of Formula II, R⁶ is OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl. In another aspect of thisembodiment, R⁵ is H, OR^(a), N(R^(a))₂, N₃, CN, SR^(a), halogen,(C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In another aspect ofthis embodiment, R⁵ is H, N₃, CN, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl. In another aspect of this embodiment, R¹ is H, methyl,CH₂OH, CH₂F, ethenyl, or ethynyl. In another aspect of this embodiment,R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl and R² and R⁴ are eachOR^(a). In another aspect of this embodiment, R¹ is H, methyl, CH₂OH,CH₂F, ethenyl, or ethynyl; R² and R⁴ are each OR^(a); and R³ and R⁵ areeach H. In another aspect of this embodiment, R⁵ is H, N₃, CN, methyl,ethenyl or ethynyl; R⁴ is OR^(a) and R³ is H. In another aspect of thisembodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl; R⁵ is Hor N₃; R⁴ is OR^(a); R³ is H; and R² is OR^(a). In another aspect ofthis embodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substitutedmethyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl;R³ and R⁵ are H and R² and R⁴ are, independently, OR^(a). In anotheraspect of this embodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl; R³ and R⁵ are H; and R² and R⁴ are each OH. Inanother aspect of this embodiment, R⁶ is OR^(a), N₃, halogen, CN,methyl, substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl; R³ and R⁵ are H; and R² and R⁴, taken together, are—O(CO)O—. In another aspect of this embodiment, R⁶ is OR^(a), N₃,halogen, CN, methyl, substituted methyl, ethenyl, substituted ethenyl,ethynyl, or substituted ethynyl; R³ is H; R² and R⁴ are independentlyOR^(a) and R⁵ is N₃. In another aspect of this of this embodiment, R⁶ isN₃, halogen, CN, methyl, hydroxymethyl, ethenyl or ethynyl. In anotheraspect of this of this embodiment, R⁶ is N₃, halogen, CN, methyl,hydroxymethyl, ethenyl or ethynyl; R¹ is H, methyl, CH₂OH, CH₂F,ethenyl, or ethynyl; and R² and R⁴ are each OR^(a). In another aspect ofthis of this embodiment, R⁶ is N₃, halogen, CN, methyl, hydroxymethyl,ethenyl or ethynyl; R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl;R² and R⁴ are each OR^(a); and R³ and R⁵ are each H.

In one embodiment of Formula II, R⁷ is H, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹ or

In a preferred aspect of this embodiment, R⁷ is H. In another preferredaspect of this embodiment, R⁷ is —C(═O)R¹¹. In another preferred aspectof this embodiment, R⁷ is —C(═O)R¹¹ wherein R¹¹ is (C₁-C₈)alkyl. Inanother preferred aspect of this embodiment, R⁷ is

In one embodiment of Formula II, X¹ is N or C—R¹⁰. In another aspect ofthis embodiment, X¹ is N. In another aspect of this embodiment, X¹ isC—R¹⁰. In another aspect of this embodiment, X² is C—H. In anotheraspect of this embodiment, X¹ is N and X² is C—H. In another aspect ofthis embodiment, X¹ is C—R¹⁰ and X² is CH. In another aspect of thisembodiment, X¹ is C—H and X² is CH. In another aspect of thisembodiment, X¹ is CR¹⁰ and R⁶ is OR^(a), N₃, halogen, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹, R¹², CN, methyl, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl. In another aspectof this embodiment, X¹ is CR¹⁰; X² is CH; and R⁶ is OR^(a), N₃, halogen,CN, methyl, substituted methyl, ethenyl, substituted ethenyl, ethynyl,or substituted ethynyl. In another aspect of this embodiment, X¹ isCR¹⁰; X² is CH; R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl; R³ isH; R² and R⁴ are each OR^(a); and R⁶ is OR^(a), N₃, halogen, CN, methyl,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl. In another aspect of this embodiment, X¹ is C—R¹⁰;X² is CH; R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl; each R³ andR⁵ is H; R² and R⁴ are each OR^(a); and R⁶ is methyl, hydroxymethyl, N₃,halogen or CN. In another aspect of this embodiment, X¹ is N and R⁶ isOR^(a), N₃, halogen, —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², CN, methyl,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl. In another aspect of this embodiment, X¹ is N; X²is CH; and R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl. Inanother aspect of this embodiment, X¹ is N; X² is CH; R¹ is H, methyl,CH₂OH, CH₂F, ethenyl, or ethynyl; R³ is H; R² and R⁴ are each OR^(a);and R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl. In another aspectof this embodiment, X¹ is N; X² is CH; R¹ is H, methyl, CH₂OH, CH₂F,ethenyl, or ethynyl; each R³ and R⁵ is H; R² and R⁴ are each OR^(a); andR⁶ is methyl, hydroxymethyl, N₃, halogen or CN.

In another embodiment of Formula II, each R⁸ is independently halogen,NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹),—CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹²,—C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹. In another aspect of this embodiment,each R⁸ is, independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹²,OR¹¹ or SR¹¹. In another aspect of this embodiment, each R⁸ is,independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl. In another aspectof this embodiment, each R⁸ is, independently, halogen, NR¹¹R¹²,N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹ and R⁹ is H, halogen, or NR¹¹R¹².In another aspect of this embodiment, each R⁸ is, independently,halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹ and R⁹ is H,halogen, or NR¹¹R¹² and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, orethynyl. In another preferred aspect of this embodiment, R⁸ is NH₂ andR⁹ is H or halogen. In another preferred aspect of this embodiment, R⁸is NH₂ and R⁹ is H or halogen and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl,or ethynyl. In another preferred aspect of this embodiment, R⁸ and R⁹are each NH₂. In another preferred aspect of this embodiment, R⁸ and R⁹are each NH₂ and R¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl. Inanother preferred aspect of this embodiment, R⁸ is OH and R⁹ is NH₂. Inanother preferred aspect of this embodiment, R⁸ is OH and R⁹ is NH₂ andR¹ is H, methyl, CH₂OH, CH₂F, ethenyl, or ethynyl.

In another embodiment of Formula II, each R¹⁰ is, independently, H,halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN,—CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹. In another aspect of thisembodiment, each R¹⁰ is H, halogen, CN or optionally substitutedheteroaryl.

In another aspect, compounds of Formula I are represented by FormulaIII:

or a pharmaceutically acceptable salt, thereof;

wherein:

R¹ is H or CH₃;

each R², R³, R⁴, or R⁵ is independently H, OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl,(C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, or aryl(C₁-C₈)alkyl;

or any two R², R³, R⁴, or R⁵ on adjacent carbon atoms when takentogether are —O(CO)O— or when taken together with the ring carbon atomsto which they are attached form a double bond;

R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂, S(O)_(n)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl,(C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substitutedalkynyl, or aryl(C₁-C₈)alkyl or R⁶ and R² when taken together are—O(CO)O—;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl of each R², R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is,independently, optionally substituted with one or more halo, hydroxy,CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more of the non-terminalcarbon atoms of each said (C₁-C₈)alkyl may be optionally replaced with—O—, —S— or —NR^(a)—; and

all remaining variables are defined as for Formula I.

In one embodiment of Formula III, R¹ is H.

In one embodiment of Formula III, R¹ is CH₃.

In one embodiment of Formula III, R² is H, OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or (C₂-C₈)substituted alkynyl. In another aspect of this embodiment, R² is H,OR^(a), N(R^(a))₂, N₃, CN, SR^(a) or halogen. In another aspect of thisembodiment, R² is H, OH, NH₂, N₃, CN, or halogen. In another aspect ofthis embodiment, R² is OR^(a) or halogen and R¹ is methyl. In anotheraspect of this embodiment, R² is OR^(a) or halogen and R¹ is H. Inanother aspect of this embodiment, R² is OR^(a) or F and R¹ is methyl.In another aspect of this embodiment, R² is OR^(a) or F and R¹ is H. Ina preferred aspect of this embodiment, R² is OH and R¹ is methyl. Inanother preferred aspect of this embodiment, R² is OR^(a) and R¹ is H.In another preferred aspect of this embodiment, R² is OH and R¹ is H. Inanother preferred aspect of this embodiment, R² is F. In anotherpreferred aspect of this embodiment, R² is OR^(a) and R¹ is methyl.

In one embodiment of Formula III, R³ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In oneaspect of this embodiment, R³ is H or F. In a preferred aspect of thisembodiment, R³ is H. In another preferred aspect of this embodiment, R³is H, R² is OR^(a) or halogen and R¹ is methyl. In another preferredaspect of this embodiment, R³ is H, R² is OR^(a) or halogen and R¹ is H.In another aspect of this embodiment, R³ is H, R² is OR^(a) or F and R¹is methyl. In another aspect of this embodiment, R³ is H, R² is OR^(a)or F and R¹ is H. In another aspect of this embodiment, R³ is H, R² isOR^(a) and R¹ is methyl. In another aspect of this embodiment, R³ is H,R² is OH and R¹ is methyl. In another aspect of this embodiment, R³ isH, R² is OR^(a) and R¹ is H. In another aspect of this embodiment, R³ isH, R² is OH and R¹ is H. In another aspect of this embodiment, each R¹,R³ and R⁵ is H and R² is OH.

In one embodiment of Formula III, R⁴ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In apreferred aspect of this embodiment, R⁴ is OR^(a). In another preferredaspect of this embodiment, R⁴ is OR^(a), R² is OR^(a) or halogen and R¹is methyl. In another preferred aspect of this embodiment, R⁴ is OR^(a),R² is OR^(a) or halogen and R¹ is H. In another preferred aspect of thisembodiment, R⁴ is OR^(a), R² is OR^(a) or halogen, R³ is H and R¹ ismethyl. In another preferred aspect of this embodiment, R⁴ is OR^(a), R²is OR^(a) or halogen, R³ is H and R¹ is H. In another preferredembodiment R⁴ is OR^(a), R² is OR^(a) or F and R¹ is methyl. In anotherpreferred embodiment R⁴ is OR^(a), R² is OR^(a) or F and R¹ is H. Inanother preferred aspect of this embodiment, R⁴ is OR^(a), R² is OR^(a)or F, R³ is H and R¹ is methyl. In another preferred aspect of thisembodiment, R⁴ and R² are, independently, OR^(a) and R¹ is methyl. Inanother preferred aspect of this embodiment, R⁴ and R² are,independently OR^(a), R³ is H and R¹ is methyl. In another preferredaspect of this embodiment, R⁴ and R², taken together, are —O(CO)O—, R³is H and R¹ is methyl. In another preferred aspect of this embodiment,R⁴ and R², taken together, are —O(CO)O—, R³ is H and R¹ is H. In anotherpreferred aspect of this embodiment, one of R⁴ or R² is OR^(a) and theother of R⁴ or R² is OH. In another preferred aspect of this embodiment,one of R⁴ or R² is OR^(a) wherein R^(a) is not H and the other of R⁴ orR² is OH, R³ is H, and R¹ is methyl. In another preferred aspect of thisembodiment, one of R⁴ or R² is OR^(a) wherein R^(a) is not H and theother of R⁴ or R² is OH, R³ is H, and R¹ is H. In another preferredaspect of this embodiment, R⁴ and R² are OH, R³ is H, and R¹ is methyl.In another preferred aspect of this embodiment, R⁴ and R² are OH, R³ isH, and R¹ is H. In another preferred aspect of this embodiment, R⁴ isOR^(a), R² is OR^(a) or F, and each R¹ and R³ is H. In another preferredaspect of this embodiment, R⁴ and R² are, independently, OR^(a) and R¹is H. In another preferred aspect of this embodiment, R⁴ and R² are,independently OR^(a) and each R¹ and R³ is H.

In one embodiment of Formula III, R⁵ is H, OR^(a), N(R^(a))₂, N₃, CN,SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. Inanother aspect of this embodiment, R⁶ is OR^(a), N(R^(a))₂, N₃, CN, NO₂,S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl and R⁵ is H, OR^(a), N(R^(a))₂,N₃, CN, SR^(a), halogen, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl.In another aspect of this embodiment, R⁶ is OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl and R⁵ is H, N₃, CN,(C₁-C₈)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In another aspect ofthis embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or (C₂-C₈)substituted alkynyl; R⁵ is H, N₃, CN, methyl, ethenyl or ethynyl; R⁴ isOR^(a) and R³ is H. In another aspect of this embodiment, R⁶ is OR^(a),N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R⁵ is H or N₃, R⁴ is OR^(a), R³ is H, and R² is For OR^(a). In another aspect of this embodiment, R⁶ is OR^(a), N₃, CN,S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R⁵ is H or N₃, R⁴ is OR^(a), R³ is H, R² is OR^(a)and R¹ is methyl. In another aspect of this embodiment, R⁶ is OR^(a),N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R³ and R⁵ are H, R² and R⁴ are, independently,OR^(a), and R¹ is methyl. In another aspect of this embodiment, R⁶ isOR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R³ and R⁵ are H, R² and R⁴ are OH, and R¹ ismethyl. In another aspect of this embodiment, R⁶ is OR^(a), N₃, CN,S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl, R¹, R³ and R⁵ are each H and R² and R⁴ are OH. Inanother aspect of this embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl, R³ and R⁵are H, R² and R⁴, taken together, are —O(CO)O—, and R¹ is methyl. Inanother aspect of this embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl, R¹, R³and R⁵ are each H and R² and R⁴, taken together, are —O(CO)O—. Inanother aspect of this embodiment, R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a),—C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹,—S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl, R¹ and R³are each H, R² and R⁴ are independently OR^(a) and R⁵ is N₃.

In one embodiment of Formula III, R² and R⁴ are each OR^(a) and at leastone of R¹, R³, or R⁵ is not H. In another aspect of this embodiment, R²and R⁴ are each OR^(a) and R¹ methyl. In another embodiment, R² and R⁴are each OR^(a) and R³ is (C₁-C₈)alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl or aryl(C₁-C₈)alkyl. In another aspect of thisembodiment, R² and R⁴ are each OR^(a) and R⁵ is OR^(a), N(R^(a))₂, N₃,CN, NO₂, S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. In another aspect ofthis embodiment, R² and R⁴ are each OR^(a) and R⁶ is OR^(a), N(R^(a))₂,N₃, CN, NO₂, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹²,—C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹²,halogen, (C₁-C₈)alkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl,(C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈) substituted alkynylor aryl(C₁-C₈)alkyl. In another aspect of this embodiment, R² and R⁴ areboth OH and R⁶ is OR^(a), N₃, CN, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen, (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, or(C₂-C₈) substituted alkynyl.

In another embodiment of Formula III, each R¹ and R² is H, one of R³ orR⁴ is OR^(a) and the other of R³ or R⁴ is (C₁-C₈)alkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl. Inanother aspect of this embodiment, each R¹ and R² is H, one of R³ or R⁴is OR^(a) and the other of R³ or R⁴ is (C₁-C₈)alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl,(C₂-C₈) substituted alkynyl or aryl(C₁-C₈)alkyl.

In another embodiment of Formula III, R⁶ is OR^(a), N(R^(a))₂, N₃, CN,NO₂, S(O)_(n)R^(a), —C(═O)R¹¹, —C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹,—S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹), —S(O)₂(OR¹¹), —SO₂NR¹¹R¹², halogen,(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C₁-C₈)alkyl. In another aspect of thisembodiment, R⁵ is H, N₃, CN, (C₁-C₈)alkyl, (C₂-C₈)alkenyl or(C₂-C₈)alkynyl. In another aspect of this embodiment, R¹ is H. Inanother aspect of this embodiment, R¹ is methyl. In another aspect ofthis embodiment, R¹ is H and R² and R⁴ are each OR^(a). In anotheraspect of this embodiment, R¹ is methyl and R² and R⁴ are each OR^(a).In another aspect of this embodiment, R¹ is H; R² and R⁴ are eachOR^(a); and R³ and R⁵ are each H. In another aspect of this embodiment,R¹ is methyl; R² and R⁴ are each OR^(a); and R³ and R⁵ are each H. Inanother aspect of this embodiment, R⁵ is H, N₃, CN, methyl, ethenyl orethynyl; R⁴ is OR^(a) and R³ is H. In another aspect of this embodiment,R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl; R⁵ is H or N₃; R⁴is OR^(a); R³ is H; and R² is OR^(a). In another aspect of thisembodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl; R³ and R⁵are H and R² and R⁴ are, independently, OR^(a). In another aspect ofthis embodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substitutedmethyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl;R³ and R⁵ are H; and R² and R⁴ are each OH. In another aspect of thisembodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substituted methyl,ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl; R³ and R⁵are H; and R² and R⁴, taken together, are —O(CO)O—. In another aspect ofthis embodiment, R⁶ is OR^(a), N₃, halogen, CN, methyl, substitutedmethyl, ethenyl, substituted ethenyl, ethynyl, or substituted ethynyl;R³ is H; R² and R⁴ are independently OR^(a) and R⁵ is N₃. In anotheraspect of this of this embodiment, R⁶ is N₃, halogen, CN, methyl,hydroxymethyl, ethenyl or ethynyl. In another aspect of this of thisembodiment, R⁶ is N₃, halogen, CN, methyl, hydroxymethyl, ethenyl orethynyl; R¹ is H; and R² and R⁴ are each OR^(a). In another aspect ofthis of this embodiment, R⁶ is N₃, halogen, CN, methyl, hydroxymethyl,ethenyl or ethynyl; R¹ is methyl; and R² and R⁴ are each OR^(a). Inanother aspect of this of this embodiment, R⁶ is N₃, halogen, CN,methyl, hydroxymethyl, ethenyl or ethynyl; R¹ is H; R² and R⁴ are eachOR^(a); and R³ and R⁵ are each H. In another aspect of this of thisembodiment, R⁶ is N₃, halogen, CN, methyl, hydroxymethyl, ethenyl orethynyl; R¹ is methyl; R² and R⁴ are each OR^(a); and R³ and R⁵ are eachH.

In one embodiment of Formula III, R⁷ is H, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)SR¹¹ or

In a preferred aspect of this embodiment, R⁷ is H. In another preferredaspect of this embodiment, R⁷ is H and R¹ is H. In another preferredaspect of this embodiment, R⁷ is —C(═O)R¹¹. In another preferred aspectof this embodiment, R⁷ is —C(═O)R¹¹ and R¹ is H. In another preferredaspect of this embodiment, R⁷ is —C(═O)R¹¹ wherein R¹¹ is (C₁-C₈)alkyl.In another preferred aspect of this embodiment, R⁷ is —C(═O)R¹¹ whereinR¹¹ is (C₁-C₈)alkyl and R¹ is H. In another preferred aspect of thisembodiment, R⁷ is

In another preferred aspect of this embodiment, R⁷ is

and R¹ is H.

In another embodiment of Formula III, each R⁸ is independently halogen,NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹),—CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹²,—C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹. In another aspect of this embodiment,each R⁸ is, independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹²,OR¹¹ or SR¹¹. In another aspect of this embodiment, each R⁸ is,independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹and R¹ is H. In another aspect of this embodiment, each R⁸ is,independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹and R¹ is methyl. In another aspect of this embodiment, each R⁸ is,independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹and R⁹ is H, halogen, or NR¹¹R¹². In another aspect of this embodiment,each R⁸ is, independently, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹²,OR¹¹ or SR¹¹ and R⁹ is H, halogen, or NR¹¹R¹² and R¹ is H. In anotheraspect of this embodiment, each R⁸ is, independently, halogen, NR¹¹R¹²,N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ or SR¹¹ and R⁹ is H, halogen, or NR¹¹R¹²and R¹ is methyl. In another preferred aspect of this embodiment, R⁸ isNH₂ and R⁹ is H or halogen. In another preferred aspect of thisembodiment, R⁸ is NH₂ and R⁹ is H or halogen and R¹ is H. In anotherpreferred aspect of this embodiment, R⁸ is NH₂ and R⁹ is H or halogenand R¹ is methyl. In another preferred aspect of this embodiment, R⁸ andR⁹ are each NH₂. In another preferred aspect of this embodiment, R⁸ andR⁹ are each NH₂ and R¹ is H. In another preferred aspect of thisembodiment, R⁸ and R⁹ are each NH₂ and R¹ is methyl. In anotherpreferred aspect of this embodiment, R⁸ is OH and R⁹ is NH₂. In anotherpreferred aspect of this embodiment, R⁸ is OH and R⁹ is NH₂ and R¹ is H.In another preferred aspect of this embodiment, R⁸ is OH and R⁹ is NH₂and R¹ is methyl.

In another embodiment of Formula III, each R¹⁰ is, independently, H,halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN,—CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,—C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹. In another aspect of thisembodiment, R⁶ is OR^(a), N₃, halogen, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², CN, methyl, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl. In another aspectof this embodiment, each R¹⁰ is H, halogen, CN or optionally substitutedheteroaryl and R⁶ is OR^(a), N₃, halogen, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², CN, methyl, substituted methyl, ethenyl,substituted ethenyl, ethynyl, or substituted ethynyl. In another aspectof this embodiment, R¹⁰ is H and R⁶ is OR^(a), N₃, halogen, CN, methyl,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl. In another aspect of this embodiment, R³ is H; R²and R⁴ are each OR^(a); and R⁶ is OR^(a), N₃, halogen, CN, methyl,substituted methyl, ethenyl, substituted ethenyl, ethynyl, orsubstituted ethynyl. In another aspect of this embodiment, each R³ andR⁵ is H; R² and R⁴ are each OR^(a); and R⁶ is methyl, hydroxymethyl, N₃,halogen or CN.

In one embodiment of Formulas I-III, R¹¹ or R¹² is independently H,(C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl,optionally substituted aryl, optionally substituted heteroaryl,—C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl or aryl(C₁-C₈)alkyl. Inanother embodiment, R¹¹ and R¹² taken together with a nitrogen to whichthey are both attached, form a 3 to 7 membered heterocyclic ring whereinany one carbon atom of said heterocyclic ring can optionally be replacedwith —O—, —S— or —NR^(a)—. Therefore, by way of example and notlimitation, the moiety —NR¹¹R¹² can be represented by the heterocycles:

and the like.

In another embodiment of Formulas I-III, R², R³, R⁴, R⁵, R⁶, R¹¹ or R¹²is, independently, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(C₁-C₈)alkyl, wherein said (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl are, independently, optionallysubstituted with one or more halo, hydroxy, CN, N₃, N(R^(a))₂ or OR^(a).Therefore, by way of example and not limitation, R², R³, R⁴, R⁵, R⁶, R¹¹or R¹² could represent moieties such as —CH(NH₂)CH₃, —CH(OH)CH2CH3,—CH(NH₂)CH(CH₃)₂, —CH₂CF₃, —(CH₂)₂CH(N₃)CH₃, —(CH₂)₆NH₂ and the like.

In another embodiment of Formula I-III, R², R³, R⁴, R⁵, R⁶, R¹¹ or R¹²is (C₁-C₈)alkyl wherein one or more of the non-terminal carbon atoms ofeach said (C₁-C₈)alkyl may be optionally replaced with —O—, —S— or—NR^(a)—. Therefore, by way of example and not limitation, R², R³, R⁴,R⁵, R⁶, R¹¹ or R¹² could represent moieties such as —CH₂OCH₃,—CH₂OCH₂CH₃, —CH₂OCH(CH₃)₂, —CH₂SCH₃, —(CH₂)₆OCH₃, —(CH₂)₆N(CH₃)₂ andthe like.

In still another embodiment, the compounds of Formula I, Formula II, orFormula III are named below in tabular format (Table 6) as compounds ofgeneral Formula IV:

wherein X1 and X2, represent substituents attached to thetetrahydrofuranyl ring as defined in Tables 1-2, below; B is a purinedefined in Table 4, below; and X³ represents a ring element of thepurine base B as described in Table 3, below.

The point of attachment of the core structure ribose is indicated ineach of the structures of X1, X2, and B. The point of attachment of thecore structure purine is indicated in each of the structures X3. Eachstructure in Tables 1-4 is represented by an alphanumeric “code”. Eachstructure of a compound of Formula IV can thus be designated in tabularform by combining the “code” representing each structural moiety usingthe following syntax: X1.X2.X3.B. Thus, for example, X1a.X2c.X3a.B1represents the following structure:

TABLE 1 X1 Structures Code Structure X1a CN X1b CH₃ X1c N₃ X1d CH₂OH

TABLE 2 X2 Structures Code Structure X2a H X2b CH₃ X2c

TABLE 3 X3 Structures Code Structure X3a —N═ X3b —CH═ X3c —CF═

TABLE 4 B Structures Code Structure B1

B2

B3

B4

TABLE 6 List of Compounds of Formula IV X1a.X2b.X3a.B1, X1a.X2b.X3a.B2,X1a.X2b.X3a.B3, X1a.X2b.X3a.B4, X1a.X2b.X3b.B1, X1a.X2b.X3b.B2,X1a.X2b.X3b.B3, X1a.X2b.X3b.B4, X1a.X2b.X3c.B1, X1a.X2b.X3c.B2,X1a.X2b.X3c.B3, X1a.X2b.X3c.B4, X1a.X2c.X3a.B1, X1a.X2c.X3a.B2,X1a.X2c.X3a.B3, X1a.X2c.X3a.B4, X1a.X2c.X3b.B1, X1a.X2c.X3b.B2,X1a.X2c.X3b.B3, X1a.X2c,X3b.B4, X1a.X2c.X3c.B1, X1a.X2c.X3c.B2,X1a.X2c.X3c.B3, X1a.X2c.X3c.B4, X1b.X2a.X3a.B1, X1b.X2a.X3a.B2,X1b.X2a.X3a.B3, X1b.X2a.X3a.B4, X1b.X2a.X3b.B1, X1b.X2a.X3b.B2,X1b.X2a.X3b.B3, X1b.X2a.X3b.B4, X1b.X2a.X3c.B1, X1b.X2a.X3c.B2,X1b.X2a.X3c.B3, X1b.X2a.X3c.B4, X1b.X2b.X3a.B1, X1b.X2b.X3a.B2,X1b.X2b.X3a.B3, X1b.X2b.X3a.B4, X1b.X2b.X3b.B1, X1b.X2b.X3b.B2,X1b.X2b.X3b.B3, X1b.X2b.X3b.B4, X1b.X2b.X3c.B1, X1b.X2b.X3c.B2,X1b.X2b.X3c.B3, X1b.X2b.X3c.B4, X1b.X2c.X3a.B1, X1b.X2c.X3a.B2,X1b.X2c.X3a.B3, X1b.X2c.X3a.B4, X1b.X2c.X3b.B1, X1b.X2c.X3b.B2,X1b.X2c.X3b.B3, X1b.X2c.X3b.B4, X1b.X2c.X3c.B1, X1b.X2c.X3c.B2,X1b.X2c.X3c.B3, X1b.X2c.X3c.B4, X1c.X2a.X3a.B1, X1c.X2a.X3a.B2,X1c.X2a.X3a.B3, X1c.X2a.X3a.B4, X1c.X2a.X3b.B1, X1c.X2a.X3b.B2,X1c.X2a.X3b.B3, X1c.X2a.X3b.B4, X1c.X2a.X3c.B1, X1c.X2a.X3c.B2,X1c.X2a.X3c.B3, X1c.X2a.X3c.B4, X1c.X2b.X3a.B1, X1c.X2b.X3a.B2,X1c.X2b.X3a.B3, X1c.X2b.X3a.B4, X1c.X2b.X3b.B1, X1c.X2b.X3b.B2,X1c.X2b.X3b.B3, X1c.X2b.X3b.B4, X1c.X2b.X3c.B1, X1c.X2b.X3c.B2,X1c.X2b.X3c.B3, X1c.X2b.X3c.B4, X1c.X2c.X3a.B1, X1c.X2c.X3a.B2,X1c.X2c.X3a.B3, X1c.X2c.X3a.B4, X1c.X2c.X3b.B1, X1c.X2c.X3b.B2,X1c.X2c.X3b.B3, X1c.X2c.X3b.B4, X1c.X2c.X3c.B1, X1c.X2c.X3c.B2,X1c.X2c.X3c.B3, X1c.X2c.X3c.B4, X1d.X2a.X3a.B1, X1d.X2a.X3a.B2,X1d.X2a.X3a.B3, X1d.X2a.X3a.B4, X1d.X2a.X3b.B1, X1d.X2a.X3b.B2,X1d.X2a.X3b.B3, X1d.X2a.X3b.B4, X1d.X2a.X3c.B1, X1d.X2a.X3c.B2,X1d.X2a.X3c.B3, X1d.X2a.X3c.B4.

In another embodiment, Formulas I-III is a compound selected from thegroup consisting of

or a pharmaceutically acceptable salt thereof.

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used hereinare intended to have the following meanings:

When trade names are used herein, applicants intend to independentlyinclude the tradename product and the active pharmaceuticalingredient(s) of the tradename product.

As used herein, “a compound of the invention” or “a compound of FormulaI” means a compound of Formula I or a pharmaceutically acceptable salt,thereof. Similarly, with respect to isolatable intermediates, the phrase“a compound of Formula (number)” means a compound of that formula andpharmaceutically acceptable salts, thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cycliccarbon atoms. For example, an alkyl group can have 1 to 20 carbon atoms(i.e, C₁-C₂₀ alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈ alkyl), or 1 to 6carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable alkyl groupsinclude, but are not limited to, methyl (Me, —CH₃), ethyl (Et, —CH₂CH₃),1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr, i-propyl,—CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃), 2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl, —CH(CH₃)CH₂CH₃),2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl (n-pentyl,—CH₂CH₂CH₂CH₂CH₃), 2-pentyl (—CH(CH₃)CH₂CH₂CH₃), 3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl (—C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl(—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂), 2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl (—CH₂CH₂CH₂CH₂CH₂CH₃), 2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl (—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl (—C(CH₃)₂CH₂CH₂CH₃), 3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl (—C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl (—CH(CH₃)C(CH₃)₃, and octyl (—(CH₂)₇CH₃).

“Alkoxy” means a group having the formula —O-alkyl, in which an alkylgroup, as defined above, is attached to the parent molecule via anoxygen atom. The alkyl portion of an alkoxy group can have 1 to 20carbon atoms (i.e., C₁-C₂₀ alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆ alkoxy). Examples ofsuitable alkoxy groups include, but are not limited to, methoxy (—O—CH₃or —OMe), ethoxy (—OCH₂CH₃ or —OEt), t-butoxy (—O—C(CH₃)₃ or —OtBu) andthe like.

“Haloalkyl” is an alkyl group, as defined above, in which one or morehydrogen atoms of the alkyl group is replaced with a halogen atom. Thealkyl portion of a haloalkyl group can have 1 to 20 carbon atoms (i.e.,C₁-C₂₀ haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂ haloalkyl), or 1to 6 carbon atoms (i.e., C₁-C₆ alkyl). Examples of suitable haloalkylgroups include, but are not limited to, —CF₃, —CHF₂, —CH₂CF₃, and thelike.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp² double bond. For example, an alkenyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkenyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkenyl). Examplesof suitable alkenyl groups include, but are not limited to, ethylene orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), and5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary orcyclic carbon atoms with at least one site of unsaturation, i.e. acarbon-carbon, sp triple bond. For example, an alkynyl group can have 2to 20 carbon atoms (i.e., C₂-C₂₀ alkynyl), 2 to 8 carbon atoms (i.e.,C₂-C₈ alkyne), or 2 to 6 carbon atoms (i.e., C₂-C₆ alkynyl). Examples ofsuitable alkynyl groups include, but are not limited to, acetylenic(—C≡CH), propargyl (—CH₂C≡CH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclichydrocarbon radical having two monovalent radical centers derived by theremoval of two hydrogen atoms from the same or two different carbonatoms of a parent alkane. For example, an alkylene group can have 1 to20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typicalalkylene radicals include, but are not limited to, methylene (—CH₂—),1,1-ethyl (—CH(CH₃)—), 1,2-ethyl (—CH₂CH₂—), 1,1-propyl (—CH(CH₂CH₃)—),1,2-propyl (—CH₂CH(CH₃)—), 1,3-propyl (—CH₂CH₂CH₂—)_(,) 1,4-butyl(—CH₂CH₂CH₂CH₂—), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkene. For example, and alkenylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkenylene radicals include, but are not limited to,1,2-ethylene (—CH═CH—).

“Alkynylene” refers to an unsaturated, branched or straight chain orcyclic hydrocarbon radical having two monovalent radical centers derivedby the removal of two hydrogen atoms from the same or two differentcarbon atoms of a parent alkyne. For example, an alkynylene group canhave 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms.Typical alkynylene radicals include, but are not limited to, acetylene(—C≡C—), propargyl (—CH₂C≡C—), and 4-pentynyl (—CH₂CH₂CH₂C≡C—).

“Amino” refers generally to a nitrogen radical which can be considered aderivative of ammonia, having the formula —N(X)₂, where each “X” isindependently H, substituted or unsubstituted alkyl, substituted orunsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl,etc. The hybridization of the nitrogen is approximately sp³. Nonlimitingtypes of amino include —NH₂, —N(alkyl)₂, —NH(alkyl), —N(carbocyclyl)₂,—NH(carbocyclyl), —N(heterocyclyl)₂, —NH(heterocyclyl), —N(aryl)₂,—NH(aryl), —N(alkyl)(aryl), —N(alkyl)(heterocyclyl),—N(carbocyclyl)(heterocyclyl), —N(aryl)(heteroaryl),—N(alkyl)(heteroaryl), etc. The term “alkylamino” refers to an aminogroup substituted with at least one alkyl group. Nonlimiting examples ofamino groups include —NH₂, —NH(CH₃), —N(CH₃)₂, —NH(CH₂CH₃), —N(CH₂CH₃)₂,—NH(phenyl), —N(phenyl)₂, —NH(benzyl), —N(benzyl)₂, etc. Substitutedalkylamino refers generally to alkylamino groups, as defined above, inwhich at least one substituted alkyl, as defined herein, is attached tothe amino nitrogen atom. Non-limiting examples of substituted alkylaminoincludes —NH(alkylene-C(O)—OH), —NH(alkylene-C(O)—O-alkyl),—N(alkylene-C(O)—OH)₂, —N(alkylene-C(O)—O-alkyl)₂, etc.

“Aryl” means an aromatic hydrocarbon radical derived by the removal ofone hydrogen atom from a single carbon atom of a parent aromatic ringsystem. For example, an aryl group can have 6 to 20 carbon atoms, 6 to14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include,but are not limited to, radicals derived from benzene (e.g., phenyl),substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groupsinclude, but are not limited to, benzyl, 2-phenylethan-1-yl,naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl,2-naphthophenylethan-1-yl and the like. The arylalkyl group can comprise7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms andthe aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp² carbon atom, is replaced with an arylradical. The aryl portion of the arylalkenyl can include, for example,any of the aryl groups disclosed herein, and the alkenyl portion of thearylalkenyl can include, for example, any of the alkenyl groupsdisclosed herein. The arylalkenyl group can comprise 8 to 20 carbonatoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of thehydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp carbon atom, is replaced with an arylradical. The aryl portion of the arylalkynyl can include, for example,any of the aryl groups disclosed herein, and the alkynyl portion of thearylalkynyl can include, for example, any of the alkynyl groupsdisclosed herein. The arylalkynyl group can comprise 8 to 20 carbonatoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the arylmoiety is 6 to 14 carbon atoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl,alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example,“substituted alkyl”, “substituted alkylene”, “substituted aryl”,“substituted arylalkyl”, “substituted heterocyclyl”, and “substitutedcarbocyclyl” means alkyl, alkylene, aryl, arylalkyl, heterocyclyl,carbocyclyl respectively, in which one or more hydrogen atoms are eachindependently replaced with a non-hydrogen substituent. Typicalsubstituents include, but are not limited to, —X, —R^(b), —O⁻, ═O,—OR^(b), —SR^(b), —S⁻, —NR^(b) ₂, —N⁺R^(b) ₃, ═NR^(b), —CX₃, —CN, —OCN,—SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂, —N₃, —NHC(═O)R^(b), —OC(═O)R^(b),—NHC(═O)NR^(b) ₂, —S(═O)₂—, —S(═O)₂OH, —S(═O)₂R^(b), —OS(═O)₂OR^(b),—S(═O)₂NR^(b) ₂, —S(═O)R^(b), —OP(═O)(OR^(b))₂, —P(═O)(OR^(b))₂,—P(═O)(O⁻)₂, —P(═O)(OH)₂, —P(O)(OR^(b))(O⁻), —C(═O)R^(b), —C(═O)X,—C(S)R^(b), —C(O)OR^(b), —C(O)O⁻, —C(S)OR^(b), —C(O)SR^(b), —C(S)SR^(b),—C(O)NR^(b) ₂, —C(S)NR^(b) ₂, —C(═NR^(b))NR^(b) ₂, where each X isindependently a halogen: F, Cl, Br, or I; and each R^(b) isindependently H, alkyl, aryl, arylalkyl, a heterocycle, or a protectinggroup or prodrug moiety. Alkylene, alkenylene, and alkynylene groups mayalso be similarly substituted. Unless otherwise indicated, when the term“substituted” is used in conjunction with groups such as arylalkyl,which have two or more moieties capable of substitution, thesubstituents can be attached to the aryl moiety, the alkyl moiety, orboth.

The term “prodrug” as used herein refers to any compound that whenadministered to a biological system generates the drug substance, i.e.,active ingredient, as a result of spontaneous chemical reaction(s),enzyme catalyzed chemical reaction(s), photolysis, and/or metabolicchemical reaction(s). A prodrug is thus a covalently modified analog orlatent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and othermoieties of the compounds of Formula I-III should be selected in orderto provide a compound which is sufficiently stable to provide apharmaceutically useful compound which can be formulated into anacceptably stable pharmaceutical composition. Compounds of Formula I-IIIwhich have such stability are contemplated as falling within the scopeof the present invention.

“Heteroalkyl” refers to an alkyl group where one or more carbon atomshave been replaced with a heteroatom, such as, O, N, or S. For example,if the carbon atom of the alkyl group which is attached to the parentmolecule is replaced with a heteroatom (e.g., O, N, or S) the resultingheteroalkyl groups are, respectively, an alkoxy group (e.g., —OCH₃,etc.), an amine (e.g., —NHCH₃, —N(CH₃)₂, etc.), or a thioalkyl group(e.g., —SCH₃). If a non-terminal carbon atom of the alkyl group which isnot attached to the parent molecule is replaced with a heteroatom (e.g.,O, N, or S) the resulting heteroalkyl groups are, respectively, an alkylether (e.g., —CH₂CH₂—O—CH₃, etc.), an alkyl amine (e.g., —CH₂NHCH₃,—CH₂N(CH₃)₂, etc.), or a thioalkyl ether (e.g., —CH₂—S—CH₃). If aterminal carbon atom of the alkyl group is replaced with a heteroatom(e.g., O, N, or S), the resulting heteroalkyl groups are, respectively,a hydroxyalkyl group (e.g., —CH₂CH₂—OH), an aminoalkyl group (e.g.,—CH₂NH₂), or an alkyl thiol group (e.g., —CH₂CH₂—SH). A heteroalkylgroup can have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms,or 1 to 6 carbon atoms. A C₁-C₆ heteroalkyl group means a heteroalkylgroup having 1 to 6 carbon atoms.

“Heterocycle” or “heterocyclyl” as used herein includes by way ofexample and not limitation those heterocycles described in Paquette, LeoA.; Principles of Modern Heterocyclic Chemistry (W. A. Benjamin, NewYork, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistryof Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons,New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment ofthe invention “heterocycle” includes a “carbocycle” as defined herein,wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replacedwith a heteroatom (e.g. O, N, or S). The terms “heterocycle” or“heterocyclyl” includes saturated rings, partially unsaturated rings,and aromatic rings (i.e., heteroaromatic rings). Substitutedheterocyclyls include, for example, heterocyclic rings substituted withany of the substituents disclosed herein including carbonyl groups. Anon-limiting example of a carbonyl substituted heterocyclyl is:

Examples of heterocycles include by way of example and not limitationpyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl,tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl,benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl,azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl,thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl,phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl,4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl,β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl,chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl,oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl,isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Still more typically, carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl,5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of aisoindole, or isoindoline, position 4 of a morpholine, and position 9 ofa carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heterocyclyl radical (i.e., aheterocyclyl-alkylene-moiety). Typical heterocyclyl alkyl groupsinclude, but are not limited to heterocyclyl-CH₂—,2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl”portion includes any of the heterocyclyl groups described above,including those described in Principles of Modern HeterocyclicChemistry. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkyl portion of theheterocyclyl alkyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkyl group comprises 3 to 20 carbonatoms, e.g., the alkyl portion of the arylalkyl group is 1 to 6 carbonatoms and the heterocyclyl moiety is 2 to 14 carbon atoms. Examples ofheterocyclylalkyls include by way of example and not limitation5-membered sulfur, oxygen, and/or nitrogen containing heterocycles suchas thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl,oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen,and/or nitrogen containing heterocycles such as piperidinylmethyl,piperazinylmethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl,pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also a sp² carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). Theheterocyclyl portion of the heterocyclyl alkenyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkenyl portion ofthe heterocyclyl alkenyl group includes any of the alkenyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkenyl portion of theheterocyclyl alkenyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkenyl group comprises 4 to 20carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenylgroup is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14carbon atoms.

“Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which oneof the hydrogen atoms bonded to a carbon atom, typically a terminal orsp³ carbon atom, but also an sp carbon atom, is replaced with aheterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety). Theheterocyclyl portion of the heterocyclyl alkynyl group includes any ofthe heterocyclyl groups described herein, including those described inPrinciples of Modern Heterocyclic Chemistry, and the alkynyl portion ofthe heterocyclyl alkynyl group includes any of the alkynyl groupsdisclosed herein. One skilled in the art will also understand that theheterocyclyl group can be attached to the alkynyl portion of theheterocyclyl alkynyl by means of a carbon-carbon bond or acarbon-heteroatom bond, with the proviso that the resulting group ischemically stable. The heterocyclyl alkynyl group comprises 4 to 20carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynylgroup is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14carbon atoms.

“Heteroaryl” refers to an aromatic heterocyclyl having at least oneheteroatom in the ring. Non-limiting examples of suitable heteroatomswhich can be included in the aromatic ring include oxygen, sulfur, andnitrogen. Non-limiting examples of heteroaryl rings include all of thosearomatic rings listed in the definition of “heterocyclyl”, includingpyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl,thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl,thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl,pyridazyl, pyrimidyl, pyrazyl, etc.

“Carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl),partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) oraromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbonatoms as a bicycle, and up to about 20 carbon atoms as a polycycle.Monocyclic carbocycles have 3 to 7 ring atoms, still more typically 5 or6 ring atoms. Bicyclic carbocycles have 7 to 12 ring atoms, e.g.,arranged as a bicyclo[4,5], [5,5], [5,6] or [6,6] system, or 9 or 10ring atoms arranged as a bicyclo[5,6] or [6,6] system, or spiro-fusedrings. Non-limiting examples of monocyclic carbocycles includecyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, 1-cyclohex-3-enyl, and phenyl. Non-limiting examplesof bicyclo carbocycles includes naphthyl, tetrahydronapthalene, anddecaline.

“Carbocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom is replaced with acarbocyclyl radical as described herein. Typical, but non-limiting,examples of carbocyclylalkyl groups include cyclopropylmethyl,cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl andcyclohexylmethyl.

“Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which ahydrogen atom (which may be attached either to a carbon atom or aheteroatom) has been replaced with an aryl group as defined herein. Thearyl groups may be bonded to a carbon atom of the heteroalkyl group, orto a heteroatom of the heteroalkyl group, provided that the resultingarylheteroalkyl group provides a chemically stable moiety. For example,an arylheteroalkyl group can have the general formulae-alkylene-O-aryl,-alkylene-O-alkylene-aryl, -alkylene-NH-aryl,-alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl,etc. In addition, any of the alkylene moieties in the general formulaeabove can be further substituted with any of the substituents defined orexemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in whicha hydrogen atom has been replaced with a heteroaryl group as definedherein. Non-limiting examples of heteroaryl alkyl include—CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl,—CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl,—CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl,—CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl,—CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl,—CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl,—CH(CH₃)-oxazolyl, —CH(CH₃)-indolyl, —CH(CH₃)-isoindolyl,—CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl,—CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl,—CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl,—CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl,—CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl,—CH(CH₃)-pyrazyl, etc.

The term “optionally substituted” in reference to a particular moiety ofthe compound of Formula I-III (e.g., an optionally substituted arylgroup) refers to a moiety wherein all substituents are hydrogen orwherein one or more of the hydrogens of the moiety may be replaced bysubstituents such as those listed under the definition of “substituted”.

The term “optionally replaced” in reference to a particular moiety ofthe compound of Formula I-III (e.g., the carbon atoms of said(C₁-C₈)alkyl may be optionally replaced by —O—, —S—, or —NR^(a)—) meansthat one or more of the methylene groups of the (C₁-C₈)alkyl may bereplaced by 0, 1, 2, or more of the groups specified (e.g., —O—, —S—, or—NR^(a)—).

The term “non-terminal carbon atom(s)” in reference to an alkyl,alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers tothe carbon atoms in the moiety that intervene between the first carbonatom of the moiety and the last carbon atom in the moiety. Therefore, byway of example and not limitation, in the alkyl moiety—CH₂(C*)H₂(C*)H₂CH₃ or alkylene moiety —CH₂(C*)H₂(C*)H₂CH₂— the C* atomswould be considered to be the non-terminal carbon atoms.

Certain Y and Y¹ alternatives are nitrogen oxides such as ⁺N(O)(R) or⁺N(O)(OR). These nitrogen oxides, as shown here attached to a carbonatom, can also be represented by charge separated groups such as

respectively, and are intended to be equivalent to the aforementionedrepresentations for the purposes of describing this invention.

“Linker” or “link” means a chemical moiety comprising a covalent bond ora chain of atoms. Linkers include repeating units of alkyloxy (e.g.polyethyleneoxy, PEG, polymethyleneoxy) and alkylamino (e.g.polyethyleneamino, Jeffamine™); and diacid ester and amides includingsuccinate, succinamide, diglycolate, malonate, and caproamide.

The terms such as “oxygen-linked”, “nitrogen-linked”, “carbon-linked”,“sulfur-linked”, or “phosphorous-linked” mean that if a bond between twomoieties can be formed by using more than one type of atom in a moiety,then the bond formed between the moieties is through the atom specified.For example, a nitrogen-linked amino acid would be bonded through anitrogen atom of the amino acid rather than through an oxygen or carbonatom of the amino acid.

Unless otherwise specified, the carbon atoms of the compounds of FormulaI-III are intended to have a valence of four. In some chemical structurerepresentations where carbon atoms do not have a sufficient number ofvariables attached to produce a valence of four, the remaining carbonsubstitutents needed to provide a valence of four should be assumed tobe hydrogen. For example,

has the same meaning as

“Protecting group” refers to a moiety of a compound that masks or altersthe properties of a functional group or the properties of the compoundas a whole. The chemical substructure of a protecting group varieswidely. One function of a protecting group is to serve as anintermediate in the synthesis of the parental drug substance. Chemicalprotecting groups and strategies for protection/deprotection are wellknown in the art. See: “Protective Groups in Organic Chemistry”,Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protectinggroups are often utilized to mask the reactivity of certain functionalgroups, to assist in the efficiency of desired chemical reactions, e gmaking and breaking chemical bonds in an ordered and planned fashion.Protection of functional groups of a compound alters other physicalproperties besides the reactivity of the protected functional group,such as the polarity, lipophilicity (hydrophobicity), and otherproperties which can be measured by common analytical tools. Chemicallyprotected intermediates may themselves be biologically active orinactive.

Protected compounds may also exhibit altered, and in some cases,optimized properties in vitro and in vivo, such as passage throughcellular membranes and resistance to enzymatic degradation orsequestration. In this role, protected compounds with intendedtherapeutic effects may be referred to as prodrugs. Another function ofa protecting group is to convert the parental drug into a prodrug,whereby the parental drug is released upon conversion of the prodrug invivo. Because active prodrugs may be absorbed more effectively than theparental drug, prodrugs may possess greater potency in vivo than theparental drug. Protecting groups are removed either in vitro, in theinstance of chemical intermediates, or in vivo, in the case of prodrugs.With chemical intermediates, it is not particularly important that theresulting products after deprotection, e.g. alcohols, be physiologicallyacceptable, although in general it is more desirable if the products arepharmacologically innocuous.

“Prodrug moiety” means a labile functional group which separates fromthe active inhibitory compound during metabolism, systemically, inside acell, by hydrolysis, enzymatic cleavage, or by some other process(Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook ofDrug Design and Development (1991), P. Krogsgaard-Larsen and H.Bundgaard, Eds. Harwood Academic Publishers, pp. 113-191). Enzymes whichare capable of an enzymatic activation mechanism with the phosphonateprodrug compounds of the invention include, but are not limited to,amidases, esterases, microbial enzymes, phospholipases, cholinesterases,and phosphases. Prodrug moieties can serve to enhance solubility,absorption and lipophilicity to optimize drug delivery, bioavailabilityand efficacy.

A prodrug moiety may include an active metabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive orlabile acyloxymethyl esters —CH₂OC(═O)R³⁰ and acyloxymethyl carbonates—CH₂C(═O)OR³⁰ where R³⁰ is C₁-C₆ alkyl, C₁-C₆ substituted alkyl, C₆-C₂₀aryl or C₆-C₂₀ substituted aryl. The acyloxyalkyl ester was used as aprodrug strategy for carboxylic acids and then applied to phosphates andphosphonates by Farquhar et al (1983) J. Pharm. Sci. 72: 324; also U.S.Pat. Nos. 4,816,570, 4,968,788, 5,663,159 and 5,792,756. In certaincompounds of the invention, a prodrug moiety is part of a phosphategroup. The acyloxyalkyl ester may be used to deliver phosphoric acidsacross cell membranes and to enhance oral bioavailability. A closevariant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester(carbonate), may also enhance oral bioavailability as a prodrug moietyin the compounds of the combinations of the invention. An exemplaryacyloxymethyl ester is pivaloyloxymethoxy, (POM) —CH₂C(═O)C(CH₃)₃. Anexemplary acyloxymethyl carbonate prodrug moiety ispivaloyloxymethylcarbonate (POC) —CH₂C(═O)OC(CH₃)₃.

The phosphate group may be a phosphate prodrug moiety. The prodrugmoiety may be sensitive to hydrolysis, such as, but not limited to thosecomprising a pivaloyloxymethyl carbonate (POC) or POM group.Alternatively, the prodrug moiety may be sensitive to enzymaticpotentiated cleavage, such as a lactate ester or a phosphonamidate-estergroup.

Aryl esters of phosphorus groups, especially phenyl esters, are reportedto enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem.37: 498). Phenyl esters containing a carboxylic ester ortho to thephosphate have also been described (Khamnei and Torrence, (1996) J. Med.Chem. 39:4109-4115). Benzyl esters are reported to generate the parentphosphonic acid. In some cases, substituents at the ortho- orpara-position may accelerate the hydrolysis. Benzyl analogs with anacylated phenol or an alkylated phenol may generate the phenoliccompound through the action of enzymes, e.g. esterases, oxidases, etc.,which in turn undergoes cleavage at the benzylic C—O bond to generatethe phosphoric acid and the quinone methide intermediate. Examples ofthis class of prodrugs are described by Mitchell et al (1992) J. Chem.Soc. Perkin Trans. 12345; Brook et al WO 91/19721. Still other benzylicprodrugs have been described containing a carboxylic ester-containinggroup attached to the benzylic methylene (Glazier et al WO 91/19721).Thio-containing prodrugs are reported to be useful for the intracellulardelivery of phosphonate drugs. These proesters contain an ethylthiogroup in which the thiol group is either esterified with an acyl groupor combined with another thiol group to form a disulfide.Deesterification or reduction of the disulfide generates the free thiointermediate which subsequently breaks down to the phosphoric acid andepisulfide (Puech et al (1993) Antiviral Res., 22: 155-174; Benzaria etal (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters have alsobeen described as prodrugs of phosphorus-containing compounds (Erion etal, U.S. Pat. No. 6,312,662).

It is to be noted that all enantiomers, diastereomers, and racemicmixtures, tautomers, polymorphs, pseudopolymorphs of compounds withinthe scope of Formula I, Formula II, or Formula III and pharmaceuticallyacceptable salts thereof are embraced by the present invention. Allmixtures of such enantiomers and diastereomers are within the scope ofthe present invention.

A compound of Formula I-III and its pharmaceutically acceptable saltsmay exist as different polymorphs or pseudopolymorphs. As used herein,crystalline polymorphism means the ability of a crystalline compound toexist in different crystal structures. The crystalline polymorphism mayresult from differences in crystal packing (packing polymorphism) ordifferences in packing between different conformers of the same molecule(conformational polymorphism). As used herein, crystallinepseudopolymorphism means the ability of a hydrate or solvate of acompound to exist in different crystal structures. The pseudopolymorphsof the instant invention may exist due to differences in crystal packing(packing pseudopolymorphism) or due to differences in packing betweendifferent conformers of the same molecule (conformationalpseudopolymorphism). The instant invention comprises all polymorphs andpseudopolymorphs of the compounds of Formula I-III and theirpharmaceutically acceptable salts.

A compound of Formula I-III and its pharmaceutically acceptable saltsmay also exist as an amorphous solid. As used herein, an amorphous solidis a solid in which there is no long-range order of the positions of theatoms in the solid. This definition applies as well when the crystalsize is two nanometers or less. Additives, including solvents, may beused to create the amorphous forms of the instant invention. The instantinvention comprises all amorphous forms of the compounds of FormulaI-III and their pharmaceutically acceptable salts.

Selected substituents comprising the compounds of Formula I-III arepresent to a recursive degree. In this context, “recursive substituent”means that a substituent may recite another instance of itself. Becauseof the recursive nature of such substituents, theoretically, a largenumber of compounds may be present in any given embodiment. For example,R^(x) comprises a R^(y) substituent. R^(y) can be R. R can be W³. W³ canbe W⁴ and W⁴ can be R or comprise substituents comprising R^(y). One ofordinary skill in the art of medicinal chemistry understands that thetotal number of such substituents is reasonably limited by the desiredproperties of the compound intended. Such properties include, by way ofexample and not limitation, physical properties such as molecularweight, solubility or log P, application properties such as activityagainst the intended target, and practical properties such as ease ofsynthesis.

By way of example and not limitation, W³ and R^(y) are recursivesubstituents in certain embodiments. Typically, each recursivesubstituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12,11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times in a given embodiment.More typically, each recursive substituent can independently occur 12 orfewer times in a given embodiment. Even more typically, each recursivesubstituent can independently occur 3 or fewer times in a givenembodiment. For example, W³ will occur 0 to 8 times, R^(y) will occur 0to 6 times in a given embodiment. Even more typically, W³ will occur 0to 6 times and R^(y) will occur 0 to 4 times in a given embodiment.

Recursive substituents are an intended aspect of the invention. One ofordinary skill in the art of medicinal chemistry understands theversatility of such substituents. To the degree that recursivesubstituents are present in an embodiment of the invention, the totalnumber will be determined as set forth above.

The modifier “about” used in connection with a quantity is inclusive ofthe stated value and has the meaning dictated by the context (e.g.,includes the degree of error associated with measurement of theparticular quantity).

The compounds of the Formula I-III may comprise a phosphate group as R⁷,which may be a prodrug moiety

wherein each Y or Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR),⁺N(O)(OR), or N—NR₂; W¹ and W², when taken together, are—Y³(C(R^(y))₂)₃Y³—; or one of W¹ or W² together with either R³ or R⁴ is—Y³— and the other of W¹ or W² is Formula Ia; or W¹ and W² are each,independently, a group of Formula Ia:

wherein:

each Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),N—NR₂, S, S—S, S(O), or S(O)₂;

each Y³ is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^(y) is independently H, F, Cl, Br, I, OH, R, —C(═Y¹)R, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR, or—N(R)C(═Y¹)N(R)₂, —SO₂NR₂, —CN, —N₃, —NO₂, —OR, a protecting group orW³; or when taken together, two R^(y) on the same carbon atom form acarbocyclic ring of 3 to 7 carbon atoms;

each R^(x) is independently R^(y), a protecting group, or the formula:

wherein:

M1a, M1c, and M1d are independently 0 or 1;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R is H, halogen, (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈)substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocycle, C₂-C₂₀ substituted heterocyclyl, arylalkyl, substitutedarylalkyl or a protecting group;

W³ is W⁴ or W⁵; W⁴ is R, —C(Y¹)R^(y), —C(Y¹)W⁵, —SO₂R^(y), or —SO₂W⁵;and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independentlysubstituted with 0 to 3 R^(y) groups.

W⁵ carbocycles and W⁵ heterocycles may be independently substituted with0 to 3 R^(y) groups. W⁵ may be a saturated, unsaturated or aromatic ringcomprising a mono- or bicyclic carbocycle or heterocycle. W⁵ may have 3to 10 ring atoms, e.g., 3 to 7 ring atoms. The W⁵ rings are saturatedwhen containing 3 ring atoms, saturated or mono-unsaturated whencontaining 4 ring atoms, saturated, or mono- or di-unsaturated whencontaining 5 ring atoms, and saturated, mono- or di-unsaturated, oraromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or abicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3heteroatoms selected from N, O, P, and S). W⁵ heterocyclic monocyclesmay have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atomsand 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycleshave 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatomsselected from N, O, and S) arranged as a bicyclo[4,5], [5,5], [5,6], or[6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2hetero atoms selected from N and S) arranged as a bicyclo[5,6] or [6,6]system. The W⁵ heterocycle may be bonded to Y² through a carbon,nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers,piperidine, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl,imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl,thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limitedto, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0to 3 R groups, as defined above. For example, substituted W⁵ carbocyclesinclude:

Examples of substituted phenyl carbocycles include:

Embodiments of

of Formula I-III compounds include substructures such as:

wherein each Y^(2b) is, independently, O or N(R). In a preferred aspectof this embodiment, each Y^(2b) is O and each R^(x) is independently:

wherein M12c is 1, 2 or 3 and each Y² is independently a bond, O, CR₂,or S. In another preferred aspect of this embodiment, one Y^(2b)—R^(x)is NH(R) and the other Y^(2b)—R^(x) is O—R^(x) wherein R^(x) is:

wherein M12c is 2. In another preferred aspect of this embodiment, eachY^(2b) is O and each R^(x) is independently:

wherein M12c is 2. In another preferred aspect of this embodiment, eachY^(2b) is O and each R^(x) is independently:

wherein M12c is 1 and Y² is a bond, O, or CR₂.

Other embodiments of

of Formulas I-III compounds include substructures such as:

wherein each Y³ is, independently, O or N(R). In a preferred aspect ofthis embodiment, each Y³ is O. In another preferred aspect of thisembodiment, the substructure is:

wherein R^(y) is W⁵ as defined herein.

Another embodiment of

of Formula I-III includes the substructures:

wherein each Y^(2c) is, independently, O, N(R^(y)) or S.

Another embodiment of

of Formula I-III compounds includes the substructures wherein one of W¹or W² together with either R³ or R⁴ is —Y³— and the other of W¹ or W² isFormula Ia. Such an embodiment is represented by a compound of FormulaIb selected from:

In a preferred aspect of the embodiment of Formula Ib, each Y and Y³ isO. In another preferred aspect of the embodiment of Formula Ib, W¹ or W²is Y^(2b)—R^(x); each Y, Y³ and Y^(2b) is O and R^(x) is:

wherein M12c is 1, 2 or 3 and each Y² is independently a bond, O, CR₂,or S. In another preferred aspect of the embodiment of Formula Ib, W¹ orW² is Y^(2b)—R^(x); each Y, Y³ and Y^(2b) is O and R^(x) is:

wherein M12c is 2. In another preferred aspect of the embodiment ofFormula Ib, W¹ or W² is Y^(2b)—R^(x); each Y, Y³ and Y^(2b) is O andR^(x) is:

wherein M12c is 1 and Y² is a bond, O, or CR₂.

Another embodiment of

of Formula I-III compounds includes a substructure:

wherein W⁵ is a carbocycle such as phenyl or substituted phenyl. Inanother aspect of this embodiment, the substructure is:

wherein Y^(2b) is O or N(R) and the phenyl carbocycle is substitutedwith 0 to 3 R groups. In another aspect of this embodiment of thesubstructure, R^(x) is:

wherein M12c is 1, 2 or 3 and each Y² is independently a bond, O, CR₂,or S.

Another embodiment of

of Formula I-III includes substructures:

The chiral carbon of the amino acid and lactate moieties may be eitherthe R or S configuration or the racemic mixture.

Another embodiment of

of Formula I-III is substructure

wherein each Y² is, independently, —O— or —NH—. In another preferredaspect of this embodiment, R^(y) is (C₁-C₈) alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈) alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl or(C₂-C₈) substituted alkynyl. In another preferred aspect of thisembodiment, R^(y) is (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl or (C₂-C₈)substituted alkynyl; and R is CH₃. In another preferred aspect of thisembodiment, R^(y) is (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl or (C₂-C₈)substituted alkynyl; R is CH₃; and each Y² is —NH—. In a preferredaspect of this embodiment, W¹ and W² are, independently,nitrogen-linked, naturally occurring amino acids or naturally occurringamino acid esters. In another preferred aspect of this embodiment, W¹and W² are, independently, naturally-occurring 2-hydroxy carboxylicacids or naturally-occurring 2-hydroxy carboxylic acid esters whereinthe acid or ester is linked to P through the 2-hydroxy group.

Another embodiment of

of Formula I, Formula II, or Formula III is substructure:

In one preferred aspect of this embodiment, each R^(x) is,independently, (C₁-C₈) alkyl. In another preferred aspect of thisembodiment, each R^(x) is, independently, C₆-C₂₀ aryl or C₆-C₂₀substituted aryl.

Another embodiment of

of Formulas I-III is substructure

wherein W¹ and W² are independently selected from one of the formulas inTables 20.1-20.37 and Table 30.1 below. The variables used in Tables20.1-20.37 (e.g., W²³, R²¹, etc.) pertain only to Tables 20.1-20.37,unless otherwise indicated.

The variables used in Tables 20.1 to 20.37 have the followingdefinitions:

each R²¹ is independently H or (C₁-C₈)alkyl;

each R²² is independently H, R²¹, R²³ or R²⁴ wherein each R²⁴ isindependently substituted with 0 to 3 R²³;

each R²³ is independently R^(23a), R^(23b), R^(23c) or R^(23d), providedthat when R²³ is bound to a heteroatom, then R²³ is R^(23c) or R^(23d);

each R^(23a) is independently F, Cl, Br, I, —CN, N₃ or —NO₂;

each R^(23b) is independently Y²¹;

each R^(23c) is independently —R^(2x), —N(R^(2x))(R^(2x)), —SR^(2x),—S(O)R^(2x); —S(O)₂R^(2x), —S(O)(OR^(2x)), —S(O)₂(OR^(2x)),—OC(═Y²¹)R^(2x), —OC(═Y²¹)OR^(2x), —OC(═Y²¹)(N(R^(2x))(R^(2x)));—SC(═Y²¹)R^(2x); —SC(═Y²¹)OR^(2x), —SC(═Y²¹)(N(R^(2x))(R^(2x))),—N(R^(2x))C(═Y²¹)R^(2x), —N(R^(2x))C(═Y²¹)OR^(2x), or—N(R^(2x))C(═Y²¹)(N(R^(2x))(R^(2x)));

each R^(23d) is independently —C(═Y²¹)R^(2x); —C(═Y²¹)OR^(2x) or—C(═Y²¹)(N(R^(2x))(R^(2x)));

each R^(2x) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl, heteroaryl; or two R^(2x) taken together with anitrogen to which they are both attached form a 3 to 7 memberedheterocyclic ring wherein any one carbon atom of said heterocyclic ringcan optionally be replaced with —O—, —S— or —NR²¹—; and wherein one ormore of the non-terminal carbon atoms of each said (C₁-C₈)alkyl may beoptionally replaced with —O—, —S— or —NR²¹—;

each R²⁴ is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl, or(C₂-C₈)alkynyl;

each R²⁵ is independently R²⁴ wherein each R²⁴ is substituted with 0 to3 R²³ groups;

each R^(25a) is independently (C₁-C₈)alkylene, (C₂-C₈)alkenylene, or(C₂-C₈)alkynylene any one of which said (C₁-C₈)alkylene,(C₂-C₈)alkenylene, or (C₂-C₈)alkynylene is substituted with 0-3 R²³groups;

each W²³ is independently W²⁴ or W²⁵;

each W²⁴ is independently R²⁵, —C(═Y²¹)R²⁵, —C(═Y²¹)W²⁵, —SO₂R²⁵, or—SO₂W²⁵;

each W²⁵ is independently carbocycle or heterocycle wherein W²⁵ isindependently substituted with 0 to 3 R²² groups; and

each Y²¹ is independently O or S.

TABLE 20.1

TABLE 20.2

TABLE 20.3

TABLE 20.4

TABLE 20.5

TABLE 20.6

TABLE 20.7

TABLE 20.8

TABLE 20.9

TABLE 20.10

58

59

60

TABLE 20.11

61

62

63

64

65

66

67

68

TABLE 20.12

69

70

71

TABLE 20.13

72

73

74

75

76

77

78

79

TABLE 20.14

80

81

82

TABLE 20.15

83

84

85

86

87

88

89

90

TABLE 20.16

91

92

93

94

95

96

97

98

TABLE 20.17

99

100

101

102

103

104

105

106

TABLE 20.18

107

108

109

TABLE 20.19

110

111

112

113

114

115

116

117

TABLE 20.20

118

119

120

TABLE 20.21

121

122

123

124

125

126

127

128

TABLE 20.22

129

130

131

TABLE 20.23

132

133

134

135

136

137

138

139

TABLE 20.24

140

141

142

143

144

145

146

147

TABLE 20.25

TABLE 20.26

TABLE 20.27

TABLE 20.28

TABLE 20.29

TABLE 20.30

TABLE 20.31

TABLE 20.32

TABLE 20.33

TABLE 20.34

TABLE 20.35

TABLE 20.36

TABLE 20.37

TABLE 30.1

Phosphate Embodiments of Compounds of Formula I-IV

By way of example and not limitation, the phosphate embodiments ofFormula I-IV may be represented by the general formula “MBF”:

Each embodiment of MBF is depicted as a substituted nucleus (Sc). Sc isdescribed in formulae A-G of Table 1.1 below, wherein Sc is a genericformula for a compound of Formula I, Formula II, or Formula III and thepoint of attachment to —P(O)Pd¹Pd² is indicated with a wavy line.

TABLE 1.1

Combinations of “Sc” and Pd¹ and Pd², independently selected from Table30.1, can be expressed in the form of Sc.Pd¹.Pd², where Sc isrepresented by the respective letter A-G from Table 1.1 and Pd¹ and Pd²are represented by the respective number from Table 30.1. Thus,A.256.256 represents the following compound:

Thereby, Table 7 lists many specific examples of phosphate prodrugs ofFormula I-IV.

TABLE 7 List of Compounds of MBF A.254.67, A.254.68, A.254.69, A.254.70,A.254.71, A.254.258, A.254.248, A.254.249, A.254.250, A.254.251,A.254.252, A.254.253, B.254.67, B.254.68, B.254.69, B.254.70, B.254.71,B.254.258, B.254.248, B.254.249, B.254.250, B.254.251, B.254.252,B.254.253, C.254.67, C.254.68, C.254.69, C.254.70, C.254.71, C.254.258,C.254.248, C.254.249, C.254.250, C.254.251, C.254.252, C.254.253,D.254.67, D.254.68, D.254.69, D.254.70, D.254.71, D.254.258, D.254.248,D.254.249, D.254.250, D.254.251, D.254.252, D.254.253, E.254.67,E.254.68, E.254.69, E.254.70, E.254.71, E.254.258, E.254.248, E.254.249,E.254.250, E.254.251, E.254.252, E.254.253, F.254.67, F.254.68,F.254.69, F.254.70, F.254.71, F.254.258, F.254.248, F.254.249,F.254.250, F.254.251, F.254.252, F.254.253, G.254.67, G.254.68,G.254.69, G.254.70, G.254.71, G.254.258, G.254.248, G.254.249,G.254.250, G.254.251, G.254.252, G.254.253, A.255.67, A.255.68,A.255.69, A.255.70, A.255.71, A.255.258, A.255.248, A.255.249,A.255.250, A.255.251, A.255.252, A.255.253, B.255.67, B.255.68,B.255.69, B.255.70, B.255.71, B.255.258, B.255.248, B.255.249,B.255.250, B.255.251, B.255.252, B.255.253, C.255.67, C.255.68,C.255.69, C.255.70, C.255.71, C.255.258, C.255.248, C.255.249,C.255.250, C.255.251, C.255.252, C.255.253, D.255.67, D.255.68,D.255.69, D.255.70, D.255.71, D.255.258, D.255.248, D.255.249,D.255.250, D.255.251, D.255.252, D.255.253, E.255.67, E.255.68,E.255.69, E.255.70, E.255.71, E.255.258, E.255.248, E.255.249,E.255.250, E.255.251, E.255.252, E.255.253, F.255.67, F.255.68,F.255.69, F.255.70, F.255.71, F.255.258, F.255.248, F.255.249,F.255.250, F.255.251, F.255.252, F.255.253, G.255.67, G.255.68,G.255.69, G.255.70, G.255.71, G.255.258, G.255.248, G.255.249,G.255.250, G.255.251, G.255.252, G.255.253, A.67.67, A.68.68, A.69.69,A.70.70, A.71.71, A.258.258, A.248.248, A.249.249, A.250.250, A.251.251,A252.252, A.253.253, B.67.67, B.68.68, B.69.69, B.70.70, B.71.71,B.258.258, B.248.248, B.249.249, B.250.250, B.251.251, B252.252,B.253.253, C.67.67, C.68.68, C.69.69, C.70.70, C.71.71, C.258.258,C.248.248, C.249.249, C.250.250, C.251.251, C252.252, C.253.253,D.67.67, D.68.68, D.69.69, D.70.70, D.71.71, D.258.258, D.248.248,D.249.249, D.250.250, D.251.251, D252.252, D.253.253, E.67.67, E.68.68,E.69.69, E.70.70, E.71.71, E.258.258, E.248.248, E.249.249, E.250.250,E.251.251, E252.252, E.253.253, F.67.67, F.68.68, F.69.69, F.70.70,F.71.71, F.258.258, F.248.248, F.249.249, F.250.250, F.251.251,F252.252, F.253.253, G.67.67, G.68.68, G.69.69, G.70.70, G.71.71,G.258.258, G.248.248, G.249.249, G.250.250, G.251.251, G252.252,G.253.253, A.256.257, B.256.257, C.256.257, D.256.257, E.256.257,F.256.257, G.256.257, A.256.254, B.256.254, C.256.254, D.256.254,E.256.254, F.256.254, G.256.254, A.256.250, B.256.250, C.256.250,D.256.250, E.256.250, F.256.250, G.256.250, A.256.69, B.256.69,C.256.69, D.256.69, E.256.69, F.256.69, G.256.69, A.256.71, B.256.71,C.256.71, D.256.71, E.256.71, F.256.71, G.256.71, A.256.255, B.256.255,C.256.255, D.256.255, E.256.255, F.256.255, G.256.255.

Embodiments of R^(x) include esters, carbamates, carbonates, thioesters,amides, thioamides, and urea groups:

Any reference to the compounds of the invention described herein alsoincludes a reference to a physiologically acceptable salt thereof.Examples of physiologically acceptable salts of the compounds of theinvention include salts derived from an appropriate base, such as analkali metal or an alkaline earth (for example, Na⁺, Li⁺, K⁺, Ca⁺² andMg⁺²), ammonium and NR₄ ⁺ (wherein R is defined herein). Physiologicallyacceptable salts of a nitrogen atom or an amino group include (a) acidaddition salts formed with inorganic acids, for example, hydrochloricacid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid,nitric acid and the like; (b) salts formed with organic acids such as,for example, acetic acid, oxalic acid, tartaric acid, succinic acid,maleic acid, fumaric acid, gluconic acid, citric acid, malic acid,ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannicacid, palmitic acid, alginic acid, polyglutamic acid,naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid,benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid,malonic acid, sulfosalicylic acid, glycolic acid,2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalicacid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine,glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucineand the like; and (c) salts formed from elemental anions for example,chlorine, bromine, and iodine. Physiologically acceptable salts of acompound of a hydroxy group include the anion of said compound incombination with a suitable cation such as Na⁺ and NR₄ ⁺.

For therapeutic use, salts of active ingredients of the compounds of theinvention will be physiologically acceptable, i.e. they will be saltsderived from a physiologically acceptable acid or base. However, saltsof acids or bases which are not physiologically acceptable may also finduse, for example, in the preparation or purification of aphysiologically acceptable compound. All salts, whether or not derivedform a physiologically acceptable acid or base, are within the scope ofthe present invention.

Finally, it is to be understood that the compositions herein comprisecompounds of the invention in their un-ionized, as well as zwitterionicform, and combinations with stoichiometric amounts of water as inhydrates.

The compounds of the invention, exemplified by Formula I-III may havechiral centers, e.g. chiral carbon or phosphorus atoms. The compounds ofthe invention thus include racemic mixtures of all stereoisomers,including enantiomers, diastereomers, and atropisomers. In addition, thecompounds of the invention include enriched or resolved optical isomersat any or all asymmetric, chiral atoms. In other words, the chiralcenters apparent from the depictions are provided as the chiral isomersor racemic mixtures. Both racemic and diastereomeric mixtures, as wellas the individual optical isomers isolated or synthesized, substantiallyfree of their enantiomeric or diastereomeric partners, are all withinthe scope of the invention. The racemic mixtures are separated intotheir individual, substantially optically pure isomers throughwell-known techniques such as, for example, the separation ofdiastereomeric salts formed with optically active adjuncts, e.g., acidsor bases followed by conversion back to the optically active substances.In most instances, the desired optical isomer is synthesized by means ofstereospecific reactions, beginning with the appropriate stereoisomer ofthe desired starting material.

The term “chiral” refers to molecules which have the property ofnon-superimposability of the mirror image partner, while the term“achiral” refers to molecules which are superimposable on their mirrorimage partner.

The term “stereoisomers” refers to compounds which have identicalchemical constitution, but differ with regard to the arrangement of theatoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers may separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., NewYork. Many organic compounds exist in optically active forms, i.e., theyhave the ability to rotate the plane of plane-polarized light. Indescribing an optically active compound, the prefixes D and L or R and Sare used to denote the absolute configuration of the molecule about itschiral center(s). The prefixes d and l, D and L, or (+) and (−) areemployed to designate the sign of rotation of plane-polarized light bythe compound, with S, (−), or 1 meaning that the compound islevorotatory while a compound prefixed with R, (+), or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer may also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which mayoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

Whenever a compound described herein is substituted with more than oneof the same designated group, e.g., “R” or “R¹”, then it will beunderstood that the groups may be the same or different, i.e., eachgroup is independently selected. Wavy lines,

, indicate the site of covalent bond attachments to the adjoiningsubstructures, groups, moieties, or atoms.

The compounds of the invention can also exist as tautomeric isomers incertain cases. Although only one delocalized resonance structure may bedepicted, all such forms are contemplated within the scope of theinvention. For example, ene-amine tautomers can exist for purine,pyrimidine, imidazole, guanidine, amidine, and tetrazole systems and alltheir possible tautomeric forms are within the scope of the invention.

One skilled in the art will recognize that thepyrrolo[1,2-f][1,2,4]triazine, imidazo[1,5-f][1,2,4]triazine,imidazo[1,2-f][1,2,4]triazine, and [1,2,4]triazolo[4,3-f][1,2,4]triazinenucleosides can exist in tautomeric forms. For example, but not by wayof limitation, structures (a) and (b) can have equivalent tautomericforms as shown below:

All possible tautomeric forms of the heterocycles in all of theembodiments disclosed herein are within the scope of the invention.Methods of Inhibition of HCV Polymerase

Another aspect of the invention relates to methods of inhibiting theactivity of HCV polymerase comprising the step of treating a samplesuspected of containing HCV with a composition of the invention.

Compositions of the invention may act as inhibitors of HCV polymerase,as intermediates for such inhibitors or have other utilities asdescribed below. The inhibitors will bind to locations on the surface orin a cavity of HCV polymerase having a geometry unique to HCVpolymerase. Compositions binding HCV polymerase may bind with varyingdegrees of reversibility. Those compounds binding substantiallyirreversibly are ideal candidates for use in this method of theinvention. Once labeled, the substantially irreversibly bindingcompositions are useful as probes for the detection of HCV polymerase.Accordingly, the invention relates to methods of detecting HCVpolymerase in a sample suspected of containing HCV polymerase comprisingthe steps of: treating a sample suspected of containing HCV polymerasewith a composition comprising a compound of the invention bound to alabel; and observing the effect of the sample on the activity of thelabel. Suitable labels are well known in the diagnostics field andinclude stable free radicals, fluorophores, radioisotopes, enzymes,chemiluminescent groups and chromogens. The compounds herein are labeledin conventional fashion using functional groups such as hydroxyl,carboxyl, sulfhydryl or amino.

Within the context of the invention, samples suspected of containing HCVpolymerase include natural or man-made materials such as livingorganisms; tissue or cell cultures; biological samples such asbiological material samples (blood, serum, urine, cerebrospinal fluid,tears, sputum, saliva, tissue samples, and the like); laboratorysamples; food, water, or air samples; bioproduct samples such asextracts of cells, particularly recombinant cells synthesizing a desiredglycoprotein; and the like. Typically the sample will be suspected ofcontaining an organism which produces HCV polymerase, frequently apathogenic organism such as HCV. Samples can be contained in any mediumincluding water and organic solvent\water mixtures. Samples includeliving organisms such as humans, and man made materials such as cellcultures.

The treating step of the invention comprises adding the composition ofthe invention to the sample or it comprises adding a precursor of thecomposition to the sample. The addition step comprises any method ofadministration as described above.

If desired, the activity of HCV polymerase after application of thecomposition can be observed by any method including direct and indirectmethods of detecting HCV polymerase activity. Quantitative, qualitative,and semiquantitative methods of determining HCV polymerase activity areall contemplated. Typically one of the screening methods described aboveare applied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

Organisms that contain HCV polymerase include the HCV virus. Thecompounds of this invention are useful in the treatment or prophylaxisof HCV infections in animals or in man.

However, in screening compounds capable of inhibiting humanimmunodeficiency viruses, it should be kept in mind that the results ofenzyme assays may not correlate with cell culture assays. Thus, a cellbased assay should be the primary screening tool.

Screens for HCV polymerase Inhibitors.

Compositions of the invention are screened for inhibitory activityagainst HCV polymerase by any of the conventional techniques forevaluating enzyme activity. Within the context of the invention,typically compositions are first screened for inhibition of HCVpolymerase in vitro and compositions showing inhibitory activity arethen screened for activity in vivo. Compositions having in vitro Ki(inhibitory constants) of less then about 5×10⁻⁶ M, typically less thanabout 1×10⁻⁷ M and preferably less than about 5×10⁻⁸ M are preferred forin vivo use.

Useful in vitro screens have been described in detail and will not beelaborated here. However, the examples describe suitable in vitroassays.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventionalcarriers and excipients, which will be selected in accord with ordinarypractice. Tablets will contain excipients, glidants, fillers, bindersand the like. Aqueous formulations are prepared in sterile form, andwhen intended for delivery by other than oral administration generallywill be isotonic. All formulations will optionally contain excipientssuch as those set forth in the “Handbook of Pharmaceutical Excipients”(1986). Excipients include ascorbic acid and other antioxidants,chelating agents such as EDTA, carbohydrates such as dextran,hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and thelike. The pH of the formulations ranges from about 3 to about 11, but isordinarily about 7 to 10.

While it is possible for the active ingredients to be administered aloneit may be preferable to present them as pharmaceutical formulations. Theformulations, both for veterinary and for human use, of the inventioncomprise at least one active ingredient, as above defined, together withone or more acceptable carriers therefor and optionally othertherapeutic ingredients. The carrier(s) must be “acceptable” in thesense of being compatible with the other ingredients of the formulationand physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administrationroutes. The formulations may conveniently be presented in unit dosageform and may be prepared by any of the methods well known in the art ofpharmacy. Techniques and formulations generally are found in Remington'sPharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). Such methodsinclude the step of bringing into association the active ingredient withthe carrier which constitutes one or more accessory ingredients. Ingeneral the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers orfinely divided solid carriers or both, and then, if necessary, shapingthe product.

Formulations of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, cachets or tabletseach containing a predetermined amount of the active ingredient; as apowder or granules; as a solution or a suspension in an aqueous ornon-aqueous liquid; or as an oil-in-water liquid emulsion or awater-in-oil liquid emulsion. The active ingredient may also beadministered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or moreaccessory ingredients. Compressed tablets may be prepared by compressingin a suitable machine the active ingredient in a free-flowing form suchas a powder or granules, optionally mixed with a binder, lubricant,inert diluent, preservative, surface active or dispersing agent. Moldedtablets may be made by molding in a suitable machine a mixture of thepowdered active ingredient moistened with an inert liquid diluent. Thetablets may optionally be coated or scored and optionally are formulatedso as to provide slow or controlled release of the active ingredienttherefrom.

For infections of the eye or other external tissues e.g. mouth and skin,the formulations are preferably applied as a topical ointment or creamcontaining the active ingredient(s) in an amount of, for example, 0.075to 20% w/w (including active ingredient(s) in a range between 0.1% and20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.),preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. Whenformulated in an ointment, the active ingredients may be employed witheither a paraffinic or a water-miscible ointment base. Alternatively,the active ingredients may be formulated in a cream with an oil-in-watercream base.

If desired, the aqueous phase of the cream base may include, forexample, at least 30% w/w of a polyhydric alcohol, i.e. an alcoholhaving two or more hydroxyl groups such as propylene glycol, butane1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol(including PEG 400) and mixtures thereof. The topical formulations maydesirably include a compound which enhances absorption or penetration ofthe active ingredient through the skin or other affected areas. Examplesof such dermal penetration enhancers include dimethyl sulphoxide andrelated analogs.

The oily phase of the emulsions of this invention may be constitutedfrom known ingredients in a known manner. While the phase may comprisemerely an emulsifier (otherwise known as an emulgent), it desirablycomprises a mixture of at least one emulsifier with a fat or an oil orwith both a fat and an oil. Preferably, a hydrophilic emulsifier isincluded together with a lipophilic emulsifier which acts as astabilizer. It is also preferred to include both an oil and a fat.Together, the emulsifier(s) with or without stabilizer(s) make up theso-called emulsifying wax, and the wax together with the oil and fatmake up the so-called emulsifying ointment base which forms the oilydispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

The choice of suitable oils or fats for the formulation is based onachieving the desired cosmetic properties. The cream should preferablybe a non-greasy, non-staining and washable product with suitableconsistency to avoid leakage from tubes or other containers. Straight orbranched chain, mono- or dibasic alkyl esters such as di-isoadipate,isocetyl stearate, propylene glycol diester of coconut fatty acids,isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate,2-ethylhexyl palmitate or a blend of branched chain esters known asCrodamol CAP may be used, the last three being preferred esters. Thesemay be used alone or in combination depending on the propertiesrequired. Alternatively, high melting point lipids such as white softparaffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprisea combination according to the invention together with one or morepharmaceutically acceptable carriers or excipients and optionally othertherapeutic agents. Pharmaceutical formulations containing the activeingredient may be in any form suitable for the intended method ofadministration. When used for oral use for example, tablets, troches,lozenges, aqueous or oil suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups or elixirs may be prepared.Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients may be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets may be uncoated or may be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsuleswhere the active ingredient is mixed with an inert solid diluent, forexample calcium phosphate or kaolin, or as soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, such aspeanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia,and dispersing or wetting agents such as a naturally-occurringphosphatide (e.g., lecithin), a condensation product of an alkyleneoxide with a fatty acid (e.g., polyoxyethylene stearate), a condensationproduct of ethylene oxide with a long chain aliphatic alcohol (e.g.,heptadecaethyleneoxycetanol), a condensation product of ethylene oxidewith a partial ester derived from a fatty acid and a hexitol anhydride(e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension mayalso contain one or more preservatives such as ethyl or n-propylp-hydroxy-benzoate, one or more coloring agents, one or more flavoringagents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient ina vegetable oil, such as arachis oil, olive oil, sesame oil or coconutoil, or in a mineral oil such as liquid paraffin. The oral suspensionsmay contain a thickening agent, such as beeswax, hard paraffin or cetylalcohol. Sweetening agents, such as those set forth above, and flavoringagents may be added to provide a palatable oral preparation. Thesecompositions may be preserved by the addition of an antioxidant such asascorbic acid.

Dispersible powders and granules of the invention suitable forpreparation of an aqueous suspension by the addition of water providethe active ingredient in admixture with a dispersing or wetting agent, asuspending agent, and one or more preservatives. Suitable dispersing orwetting agents and suspending agents are exemplified by those disclosedabove. Additional excipients, for example sweetening, flavoring andcoloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, a mineral oil, such as liquid paraffin, ora mixture of these. Suitable emulsifying agents includenaturally-occurring gums, such as gum acacia and gum tragacanth,naturally-occurring phosphatides, such as soybean lecithin, esters orpartial esters derived from fatty acids and hexitol anhydrides, such assorbitan monooleate, and condensation products of these partial esterswith ethylene oxide, such as polyoxyethylene sorbitan monooleate. Theemulsion may also contain sweetening and flavoring agents. Syrups andelixirs may be formulated with sweetening agents, such as glycerol,sorbitol or sucrose. Such formulations may also contain a demulcent, apreservative, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of asterile injectable preparation, such as a sterile injectable aqueous oroleaginous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butane-diol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

The amount of active ingredient that may be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans maycontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which may varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion may contain from about 3 to 500 μg of theactive ingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of 0.5 to 20%, advantageously 0.5 to10%, and particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration may be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns, such as0.5, 1, 30, 35 etc., which is administered by rapid inhalation throughthe nasal passage or by inhalation through the mouth so as to reach thealveolar sacs. Suitable formulations include aqueous or oily solutionsof the active ingredient. Formulations suitable for aerosol or drypowder administration may be prepared according to conventional methodsand may be delivered with other therapeutic agents such as compoundsheretofore used in the treatment or prophylaxis of HCV infections asdescribed below.

Formulations suitable for vaginal administration may be presented aspessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining in addition to the active ingredient such carriers as areknown in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The formulations are presented in unit-dose or multi-dose containers,for example sealed ampoules and vials, and may be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water for injection, immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above the formulations of this invention may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefor.

Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered orally, parenterally or by any otherdesired route.

Compounds of the invention are used to provide controlled releasepharmaceutical formulations containing as active ingredient one or morecompounds of the invention (“controlled release formulations”) in whichthe release of the active ingredient are controlled and regulated toallow less frequency dosing or to improve the pharmacokinetic ortoxicity profile of a given active ingredient.

Effective dose of active ingredient depends at least on the nature ofthe condition being treated, toxicity, whether the compound is beingused prophylactically (lower doses) or against an active viralinfection, the method of delivery, and the pharmaceutical formulation,and will be determined by the clinician using conventional doseescalation studies. It can be expected to be from about 0.0001 to about100 mg/kg body weight per day; typically, from about 0.01 to about 10mg/kg body weight per day; more typically, from about 0.01 to about 5mg/kg body weight per day; most typically, from about 0.05 to about 0.5mg/kg body weight per day. For example, the daily candidate dose for anadult human of approximately 70 kg body weight will range from 1 mg to1000 mg, preferably between 5 mg and 500 mg, and may take the form ofsingle or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the activeingredients) are administered by any route appropriate to the conditionto be treated. Suitable routes include oral, rectal, nasal, topical(including buccal and sublingual), vaginal and parenteral (includingsubcutaneous, intramuscular, intravenous, intradermal, intrathecal andepidural), and the like. It will be appreciated that the preferred routemay vary with for example the condition of the recipient. An advantageof the compounds of this invention is that they are orally bioavailableand can be dosed orally.

Combination Therapy

Compositions of the invention are also used in combination with otheractive ingredients. Preferably, the other active therapeutic ingredientsor agents are interferons, ribavirin analogs, NS3 protease inhibitors,NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors,hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs fortreating HCV.

Combinations of the compounds of Formula I-III are typically selectedbased on the condition to be treated, cross-reactivities of ingredientsand pharmaco-properties of the combination. For example, when treatingan infection (e.g., HCV), the compositions of the invention are combinedwith other active therapeutic agents (such as those described herein).

Suitable active therapeutic agents or ingredients which can be combinedwith the compounds of Formula I-III can include interferons, e.g.,pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFNalpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif,locteron, AVI-005, PEG-infergen, pegylated IFN-beta, oral interferonalpha, feron, reaferon, intermax alpha, r-IFN-beta, infergen+actimmune,IFN-omega with DUROS, and albuferon; ribavirin analogs, e.g., rebetol,copegus, VX-497, and viramidine (taribavirin); NS5a inhibitors, e.g.,A-831, A-689 and BMS-790052; NS5b polymerase inhibitors, e.g., NM-283,valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608,NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL-2125; NS3 proteaseinhibitors, e.g., SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN-191, andBILN-2065; alpha-glucosidase 1 inhibitors, e.g., MX-3253 (celgosivir)and UT-231B; hepatoprotectants, e.g., IDN-6556, ME 3738, MitoQ, andLB-84451; non-nucleoside inhibitors of HCV, e.g., benzimidazolederivatives, benzo-1,2,4-thiadiazine derivatives, and phenylalaninederivatives; and other drugs for treating HCV, e.g., zadaxin,nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C,EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17, KPE02003002, actilon(CPG-10101), KRN-7000, civacir, G1-5005, ANA-975, XTL-6865, ANA 971,NOV-205, tarvacin, EHC-18, and NIM811.

In yet another embodiment, the present application disclosespharmaceutical compositions comprising a compound of the presentinvention, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, in combination with at least one additional therapeutic agent,and a pharmaceutically acceptable carrier or excipient.

According to the present invention, the therapeutic agent used incombination with the compound of the present invention can be any agenthaving a therapeutic effect when used in combination with the compoundof the present invention. For example, the therapeutic agent used incombination with the compound of the present invention can beinterferons, ribavirin analogs, NS3 protease inhibitors, NS5ainhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors,hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs fortreating HCV.

In another embodiment, the present application provides pharmaceuticalcompositions comprising a compound of the present invention, or apharmaceutically acceptable salt, solvate, and/or ester thereof, incombination with at least one additional therapeutic agent selected fromthe group consisting of pegylated rIFN-alpha 2b, pegylated rIFN-alpha2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha,infergen, rebif, locteron, AVI-005, PEG-infergen, pegylated IFN-beta,oral interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta,infergen+actimmune, IFN-omega with DUROS, albuferon, rebetol, copegus,VX-497, viramidine (taribavirin), A-831, A-689, NM-283, valopicitabine,R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608, NM-107, R7128,VCH-759, PF-868554, GSK625433, XTL-2125, SCH-503034 (SCH-7), VX-950(Telaprevir), ITMN-191, and BILN-2065, MX-3253 (celgosivir), UT-231B,IDN-6556, ME 3738, MitoQ, and LB-84451, benzimidazole derivatives,benzo-1,2,4-thiadiazine derivatives, and phenylalanine derivatives,zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025,VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17,KPE02003002, actilon (CPG-10101), KRN-7000, civacir, G1-5005, ANA-975,XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811 and apharmaceutically acceptable carrier or excipient.

In yet another embodiment, the present application provides acombination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of thepresent invention, or a pharmaceutically acceptable salt, solvate, orester thereat and

b) a second pharmaceutical composition comprising at least oneadditional therapeutic agent selected from the group consisting of HIVprotease inhibiting compounds, HIV non-nucleoside inhibitors of reversetranscriptase, HIV nucleoside inhibitors of reverse transcriptase, HIVnucleotide inhibitors of reverse transcriptase, HIV integraseinhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors,NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors,hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs fortreating HCV, and combinations thereof.

Combinations of the compounds of Formula I-III and additional activetherapeutic agents may be selected to treat patients infected with HCVand other conditions such as HIV infections. Accordingly, the compoundsof Formula I-III may be combined with one or more compounds useful intreating HIV, for example HIV protease inhibiting compounds, HIVnon-nucleoside inhibitors of reverse transcriptase, HIV nucleosideinhibitors of reverse transcriptase, HIV nucleotide inhibitors ofreverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4inhibitors, gp120 inhibitors, CCR5 inhibitors, interferons, ribavirinanalogs, NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleosideinhibitors of HCV, and other drugs for treating HCV.

More specifically, one or more compounds of the present invention may becombined with one or more compounds selected from the group consistingof 1) HIV protease inhibitors, e.g., amprenavir, atazanavir,fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir+ritonavir,nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126,TMC-114, mozenavir (DMP-450), JE-2147 (AG1776), AG1859, DG35, L-756423,R00334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG17, PPL-100, 2) aHIV non-nucleoside inhibitor of reverse transcriptase, e.g.,capravirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150,and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773,UK-453,061, RDEA806, 3) a HIV nucleoside inhibitor of reversetranscriptase, e.g., zidovudine, emtricitabine, didanosine, stavudine,zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine,MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudinetidoxil, fosalvudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461,abacavir+lamivudine, abacavir+lamivudine+zidovudine,zidovudine+lamivudine, 4) a HIV nucleotide inhibitor of reversetranscriptase, e.g., tenofovir, tenofovir disoproxilfumarate+emtricitabine, tenofovir disoproxilfumarate+emtricitabine+efavirenz, and adefovir, 5) a HIV integraseinhibitor, e.g., curcumin, derivatives of curcumin, chicoric acid,derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives ofaurintricarboxylic acid, caffeic acid phenethyl ester, derivatives ofcaffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin,quercetin, derivatives of quercetin, S-1360, zintevir (AR-177),L-870812, and L-870810, MK-0518 (raltegravir), BMS-707035, MK-2048,BA-011, BMS-538158, GSK364735C, 6) a gp41 inhibitor, e.g., enfuvirtide,sifuvirtide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX, and REP 9,7) a CXCR4 inhibitor, e.g., AMD-070, 8) an entry inhibitor, e.g., SP01A,TNX-355, 9) a gp120 inhibitor, e.g., BMS-488043 and BlockAide/CR, 10) aG6PD and NADH-oxidase inhibitor, e.g., immunitin, 10) a CCR5 inhibitor,e.g., aplaviroc, vicriviroc, INCB9471, PRO-140, INCB15050, PF-232798,CCR5 mAb004, and maraviroc, 11) an interferon, e.g., pegylatedrIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL,rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005,PEG-infergen, pegylated IFN-beta, oral interferon alpha, feron,reaferon, intermax alpha, r-IFN-beta, infergen+actimmune, IFN-omega withDUROS, and albuferon, 12) ribavirin analogs, e.g., rebetol, copegus,VX-497, and viramidine (taribavirin) 13) NS5a inhibitors, e.g., A-831,A-689 and BMS-790052, 14) NS5b polymerase inhibitors, e.g., NM-283,valopicitabine, R1626, PSI-6130 (R1656), HCV-796, BILB 1941, MK-0608,NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL-2125, 15) NS3protease inhibitors, e.g., SCH-503034 (SCH-7), VX-950 (Telaprevir),ITMN-191, and BILN-2065, 16) alpha-glucosidase 1 inhibitors, e.g.,MX-3253 (celgosivir) and UT-231B, 17) hepatoprotectants, e.g., IDN-6556,ME 3738, MitoQ, and LB-84451, 18) non-nucleoside inhibitors of HCV,e.g., benzimidazole derivatives, benzo-1,2,4-thiadiazine derivatives,and phenylalanine derivatives, 19) other drugs for treating HCV, e.g.,zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025,VGX-410C, EMZ-702, AVI 4065, bavituximab, oglufanide, PYN-17,KPE02003002, actilon (CPG-10101), KRN-7000, civacir, G1-5005, ANA-975,XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and NIM811, 19)pharmacokinetic enhancers, e.g., BAS-100 and SPI452, 20)RNAse Hinhibitors, e.g., ODN-93 and ODN-112, 21) other anti-HIV agents, e.g.,VGV-1, PA-457 (bevirimat), ampligen, HRG214, cytolin, polymun, VGX-410,KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab),PBS119, ALG889, and PA-1050040.

It is also possible to combine any compound of the invention with one ormore other active therapeutic agents in a unitary dosage form forsimultaneous or sequential administration to a patient. The combinationtherapy may be administered as a simultaneous or sequential regimen.When administered sequentially, the combination may be administered intwo or more administrations.

Co-administration of a compound of the invention with one or more otheractive therapeutic agents generally refers to simultaneous or sequentialadministration of a compound of the invention and one or more otheractive therapeutic agents, such that therapeutically effective amountsof the compound of the invention and one or more other activetherapeutic agents are both present in the body of the patient.

Co-administration includes administration of unit dosages of thecompounds of the invention before or after administration of unitdosages of one or more other active therapeutic agents, for example,administration of the compounds of the invention within seconds,minutes, or hours of the administration of one or more other activetherapeutic agents. For example, a unit dose of a compound of theinvention can be administered first, followed within seconds or minutesby administration of a unit dose of one or more other active therapeuticagents. Alternatively, a unit dose of one or more other therapeuticagents can be administered first, followed by administration of a unitdose of a compound of the invention within seconds or minutes. In somecases, it may be desirable to administer a unit dose of a compound ofthe invention first, followed, after a period of hours (e.g., 1-12hours), by administration of a unit dose of one or more other activetherapeutic agents. In other cases, it may be desirable to administer aunit dose of one or more other active therapeutic agents first,followed, after a period of hours (e.g., 1-12 hours), by administrationof a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic”, i.e.the effect achieved when the active ingredients used together is greaterthan the sum of the effects that results from using the compoundsseparately. A synergistic effect may be attained when the activeingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined formulation; (2) delivered by alternationor in parallel as separate formulations; or (3) by some other regimen.When delivered in alternation therapy, a synergistic effect may beattained when the compounds are administered or delivered sequentially,e.g. in separate tablets, pills or capsules, or by different injectionsin separate syringes. In general, during alternation therapy, aneffective dosage of each active ingredient is administered sequentially,i.e. serially, whereas in combination therapy, effective dosages of twoor more active ingredients are administered together. A synergisticanti-viral effect denotes an antiviral effect which is greater than thepredicted purely additive effects of the individual compounds of thecombination.

In still yet another embodiment, the present application provides formethods of inhibiting HCV polymerase in a cell, comprising: contacting acell infected with HCV with an effective amount of a compound of FormulaI-III, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, whereby HCV polymerase is inhibited.

In still yet another embodiment, the present application provides formethods of inhibiting HCV polymerase in a cell, comprising: contacting acell infected with HCV with an effective amount of a compound of FormulaI-III, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, and at least one additional active therapeutic agent, wherebyHCV polymerase is inhibited.

In still yet another embodiment, the present application provides formethods of inhibiting HCV polymerase in a cell, comprising: contacting acell infected with HCV with an effective amount of a compound of FormulaI-III, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, and at least one additional active therapeutic agent selectedfrom the group consisting of interferons, ribavirin analogs, NS3protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors,cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors ofHCV, and other drugs for treating HCV.

In still yet another embodiment, the present application provides formethods of treating HCV in a patient, comprising: administering to thepatient a therapeutically effective amount of a compound of FormulaI-III, or a pharmaceutically acceptable salt, solvate, and/or esterthereof.

In still yet another embodiment, the present application provides formethods of treating HCV in a patient, comprising: administering to thepatient a therapeutically effective amount of a compound of Formula or apharmaceutically acceptable salt, solvate, and/or ester thereof, and atleast one additional active therapeutic agent, whereby HCV polymerase isinhibited.

In still yet another embodiment, the present application provides formethods of treating HCV in a patient, comprising: administering to thepatient a therapeutically effective amount of a compound of FormulaI-III, or a pharmaceutically acceptable salt, solvate, and/or esterthereof, and at least one additional active therapeutic agent selectedfrom the group consisting of interferons, ribavirin analogs, NS3protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors,cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors ofHCV, and other drugs for treating HCV.

In still yet another embodiment, the present application provides forthe use of a compound of the present invention, or a pharmaceuticallyacceptable salt, solvate, and/or ester thereof, for the preparation of amedicament for treating an HCV infection in a patient.

Metabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivometabolic products of the compounds described herein, to the extent suchproducts are novel and unobvious over the prior art. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes novel andunobvious compounds produced by a process comprising contacting acompound of this invention with a mammal for a period of time sufficientto yield a metabolic product thereof. Such products typically areidentified by preparing a radiolabelled (e.g. ¹⁴C or ³H) compound of theinvention, administering it parenterally in a detectable dose (e.g.greater than about 0.5 mg/kg) to an animal such as rat, mouse, guineapig, monkey, or to man, allowing sufficient time for metabolism to occur(typically about 30 seconds to 30 hours) and isolating its conversionproducts from the urine, blood or other biological samples. Theseproducts are easily isolated since they are labeled (others are isolatedby the use of antibodies capable of binding epitopes surviving in themetabolite). The metabolite structures are determined in conventionalfashion, e.g. by MS or NMR analysis. In general, analysis of metabolitesis done in the same way as conventional drug metabolism studieswell-known to those skilled in the art. The conversion products, so longas they are not otherwise found in vivo, are useful in diagnostic assaysfor therapeutic dosing of the compounds of the invention even if theypossess no HCV polymerase inhibitory activity of their own.

Recipes and methods for determining stability of compounds in surrogategastrointestinal secretions are known. Compounds are defined herein asstable in the gastrointestinal tract where less than about 50 molepercent of the protected groups are deprotected in surrogate intestinalor gastric juice upon incubation for 1 hour at 37° C. Simply because thecompounds are stable to the gastrointestinal tract does not mean thatthey cannot be hydrolyzed in vivo. The prodrugs of the inventiontypically will be stable in the digestive system but may besubstantially hydrolyzed to the parental drug in the digestive lumen,liver or other metabolic organ, or within cells in general.

EXAMPLES

Certain abbreviations and acronyms are used in describing theexperimental details. Although most of these would be understood by oneskilled in the art, Table 1 contains a list of many of theseabbreviations and acronyms.

TABLE 1 List of abbreviations and acronyms. Abbreviation Meaning Ac₂Oacetic anhydride AIBN 2,2′-azobis(2-methylpropionitrile) Bn benzyl BnBrbenzylbromide BSA bis(trimethylsilyl)acetamide BzCl benzoyl chloride CDIcarbonyl diimidazole DABCO 1,4-diazabicyclo[2.2.2]octane DBN1,5-diazabicyclo[4.3.0]nonene-5 DDQ2,3-dichloro-5,6-dicyano-1,4-benzoquinone DBU1,5-diazabicyclo[5.4.0]undecene-5 DCA dichloroacetamide DCCdicyclohexylcarbodiimide DCM dichloromethane DMAP4-dimethylaminopyridine DME 1,2-dimethoxyethane DMTCl dimethoxytritylchloride DMSO dimethylsulfoxide DMTr 4,4′-dimethoxytrityl DMFdimethylformamide EtOAc ethyl acetate ESI electrospray ionization HMDShexamethyldisilazane HPLC High pressure liquid chromatography LDAlithium diisopropylamide LRMS low resolution mass spectrum MCPBAmeta-chloroperbenzoic acid MeCN acetonitrile MeOH methanol MMTC monomethoxytrityl chloride m/z or m/e mass to charge ratio MH⁺ mass plus 1MH⁻ mass minus 1 MsOH methanesulfonic acid MS or ms mass spectrum NBSN-bromosuccinimide rt or r.t. room temperature TBAF tetrabutylammoniumfluoride TMSCl chlorotrimethylsilane TMSBr bromotrimethylsilane TMSIiodotrimethylsilane TEA triethylamine TBA tributylamine TBAPtributylammonium pyrophosphate TBSCl t-butyldimethylsilyl chloride TEABtriethylammonium bicarbonate TFA trifluoroacetic acid TLC or tlc thinlayer chromatography Tr triphenylmethyl Tol 4-methylbenzoyl δ parts permillion down field from tetramethylsilane

Preparation of Compounds

Compound 1a-1f

To a solution of 1a (22.0 g, 54.9 mmol, prepared according to theprocedures described in J.O.C., 2004, 6257) in methanol (300 mL) wasdropwise added acetyl chloride (22 mL) at 0° C. using a dropping funnelover a period of 30 min. and then stirred at room temperature for 16 h.The mixture was concentrated, re-dissolved in ethyl acetate (400 mL),washed with ice-cold 2 N NaOH, and concentrated to dryness, affordingthe crude methyl ether 1b as an oil. MS=437.2 (M+Na⁺).

To a solution of 1b (obtained from the previous step) in methanol (300mL) was added 0.5 M sodium methoxide solution in methanol (20 mL, 10mmol), and stirred for 16 h at room temperature. The reaction wasquenched with 4.0 N HCl solution in dioxane (2.5 mL, 10 mmol). Themixture was then concentrated, affording the crude 1c. MS=201.0 (M+Na⁺).

A mixture of 1c (obtained from the previous step), Tritron X-405 (70% inwater, 6.0 g), 50% KOH (in water, 85 g) in toluene (500 mL) was heatedto reflux with a Dean-Stark trap attached. After 1 h collecting ˜25 mLof water, benzyl chloride (33 g, 260 mmol) was added and continued toreflux with stirring for 16 h. The mixture was then cooled andpartitioned between ethyl acetate (400 mL) and water (300 mL). Theorganic layer was washed with water (300 mL), and concentrated. Theresidue was purified by silica gel column chromatography (˜20%EtOAc/hexanes), affording the methyl ether 1d as an oil (22.0 g, 89% inthree steps). ¹1-1 NMR (300 MHz, CDCl₃): δ 7.3 (m, 15H), 4.5-4.9 (m,7H), 4.37 (m, 1H), 3.87 (d, 1H), 3.56 (m, 2H), 3.52 (s, 3H), 1.40 (s,3H).

To a solution of 1d (22.0 g, 49.0 mmol) in acetic acid (110 mL) wasadded ˜3 M sulfuric acid (prepared by mixing 4.8 g of concentratedsulfuric acid with 24 mL of water) and stirred at 70° C. for 8 h. Themixture was concentrated to a volume of ˜20 mL, and partitioned betweenethyl acetate and ice-cold 2N NaOH. The ethyl acetate layer wasconcentrated, and purified by silica gel column chromatography (˜35%EtOAc/hexanes), affording 1e as an oil (17.0 g, 80%). MS=457.2 (M+Na⁺).

To a solution of 1e (45 g, 104 mmol) in DMSO (135 mL) was dropwise addedacetic anhydride (90 mL, 815 mmol) at room temperature under argon. Themixture was stirred for 16 h at room temperature, and then poured intoice-water (1 L) while stirring. After ice was completely melted (˜30min), ethyl acetate (˜500 mL) was added. The organic layer wasseparated. This extraction process was repeated three times (3×500 mL).The organic extracts were combined and concentrated. The residue waspurified by silica gel column chromatography (˜20% EtOAc/hexanes),affording if as an oil (39 g, 88%). ¹H NMR (300 MHz, DMSO-d₆): δ 7.3 (m,15H), 4.4-4.8 (m, 7H), 4.08 (d, J=7.5 Hz, 1H), 3.75 (dd, J=2, 4, 11.4Hz, 1H), 3.64 (dd, J=5.4, 11.4 Hz, 1H), 1.51 (s, 3H).

Compound 2

To a dry, argon purged round bottom flask (100 mL) were added7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (234 mg, 1.10 mmol)(prepared according to WO2007056170) and anhydrous THF (1.5 mL). TMSCl(276 μL, 2.2 mmol) was then added and the reaction mixture stirred for 2h. The flask was placed into a dry ice/acetone bath (˜−78° C.) and BuLi(2.5 mL, 4.0 mmol, 1.6M in hexanes) was added dropwise. After 1 h, asolution of if (432.5 mg, 1.0 mmol) in THF was cooled to 0° C. and thenadded to the reaction flask dropwise. After 1 h of stirring at −78° C.,the flask was warmed to 0° C. and sat. NH₄Cl (5 mL) was added to quenchthe reaction. The organics were extracted using EtOAc (3×10 mL) and thecombined organic layers were dried using MgSO₄. The solvent was removedunder reduced pressure and the crude material was purified using flashchromatography (hexanes/EtOAc). 560 mg (99%) of 2a was isolated as amixture of two anomers. LC/MS=567.2 (M+H⁺). ¹H NMR (300 MHz, CDCl₃): δ7.85 (m, 1H), 7.27 (m, 15H), 7.01 (m, 1H), 6.51 (m, 1H), 4.66 (m, 8H),4.40 (m, 2H), 3.79 (m, 3H), 1.62 (s, 2′-CH₃ from the one anomer), 1.18(s, 2′-CH₃ from the other anomer).

To a dry, argon purged round bottom flask (50 mL) were added compound 2a(185 mg, 0.33 mmol) and anhydrous dichloromethane (10 mL). The flask wasplaced into a dry ice/acetone bath (˜−78° C.) and the solution stirredfor 10 min. BBr₃ (0.25 mL, 0.25 mmol, 1.0 M in DCM) was then added andthe reaction continued to stir at −78° C. until complete disappearanceof the starting material. After 1 h, a solution of pyridine (2 mL) inMeOH (10 mL) was added and the flask was warmed to room temperature. Thesolvent was removed under reduced pressure and the crude material wasre-dissolved in MeOH. After this process was repeated two more times,the crude material was then dissolved in water and purified using aGilson Preparatory HPLC system (acetonitrile/H₂O). 49 mg (50%) ofCompound 2 was isolated as an isomeric mixture. LC/MS=297.1 (M+H⁺). ¹HNMR (300 MHz, D₂O): δ 7.68 (m, 1H), 6.80 (m, 2H), 4.04 (m, 2H), 3.78 (m,2H), 3.65 (m, 1H), 1.30 (s, 2′-CH₃), 0.80 (s, 2′-CH₃).

Compound 3

To a dry, argon purged round bottom flask (100 mL) were added Compound 2(12 mg, 0.04 mmol) (2) and anhydrous MeOH (5 mL). Acetic acid (5 mL) wasthen added and the reaction stirred overnight at room temperature.Saturated NaHCO₃ was added to neutralize the reaction mixture and thecrude material was purified using a Gilson Preparatory HPLC system(acetonitrile-H₂O). 2 mg (16%) of the desired material Compound 3 wasisolated. LC/MS=311.2 (M+H⁺). ¹H NMR (300 MHz, D₂O): δ 7.71 (s, 1H),6.78 (s, 2H), 3.98 (m, 1H), 3.83 (dd, 1H), 3.74 (dd, 1H), 3.62 (d, 1H),2.94 (s, 3H), 0.76 (s, 3H). The other alpha-isomer was also isolated; ¹HNMR (300 MHz, D₂O): δ 7.65 (s, 1H), 6.78 (d, 1H), 6.75 (d, 1H), 4.03 (m,2H), 3.77 (dd, 1H), 3.59 (d, 1H), 2.95 (s, 3H), 1.31 (s, 3H).

Compound 4

To a dry, argon purged round bottom flask (50 mL) were added compound 2a(220 mg, 0.39 mmol) and anhydrous dichloromethane (10 mL). The flask wasplaced into a dry ice/acetone bath (˜−78° C.) and the solution stirredfor 10 min. BF₃-Et₂O (0.10 mL) was added dropwise and the reactionstirred for 10 min. AlMe₃ (0.58 mL, 1.16 mmol, 2.0 M in toluene) wasthen added. After a few minutes, the dry ice/acetone bath was removedand the reaction mixture warmed to room temperature over 4 h. A solutionof pyridine (2 mL) in MeOH (10 mL) was added and the solvent was removedunder reduced pressure. The crude material was purified using flashchromatography (hexanes/EtOAc). 164 mg (74%) of the desired material 4awas isolated. LC/MS=565.2 (M+Fr). ¹H NMR (300 MHz, CD₃OD): δ 7.71 (s,1H), 7.32 (m, 15H), 7.02 (m, 1H), 6.78 (m, 1H), 4.62 (m, 8H), 4.21 (m,1H), 4.04 (m, 1H), 3.84 (m, 1H), 1.95 (s, 3H), 1.10 (s, 3H).

To a dry, argon purged round bottom flask (50 mL) were added compound 4a(164 mg, 0.29 mmol) and glacial acetic acid (10 mL). Pd/C (100 mg, 10%by wt.) was then added and the flask was equipped with a ballooncontaining hydrogen gas. The flask was purged two times to ensure all ofthe argon had been replaced with hydrogen. The reaction was allowed tostir at room temperature overnight. The reaction mixture was thenneutralized using NaHCO₃ and filtered to remove the catalyst. The crudematerial was purified using a Gilson Preparatory HPLC system(acetonitrile/H₂O). 6 mg (7%) of the desired material Compound 4 wasisolated. LC/MS=295.1 (M+H⁺). ¹H NMR (300 MHz, D₂O): δ 7.66 (s, 1H),6.72 (m, 1H), 6.64 (m, 1H), 3.93 (m, 1H), 3.76 (m, 3H), 1.63 (s, 3H),0.76 (s, 3H).

Compound 5

To a solution of compound 2a (1 g, 1.77 mmol) in CH₂Cl₂ (20 mL) at 0° C.was added TMSCN (1.4 mL, 10.5 mmol) and BF₃-Et₂O (1 mL, 8.1 mmol). Thereaction mixture was stirred at 0° C. for 0.5 h, then at roomtemperature for additional 0.5 h. The reaction was quenched with NaHCO₃at 0° C., and diluted with CH₃CO₂Et. The organic phase was separated,washed with brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel, eluted withCH₃CO₂Et-hexanes (1:1 to 2:1), to give the desired compound 5a (620 mg,61%) as an isomeric mixture. MS=576.1 (M+H⁺).

To a solution of compound 5a (150 mg, 0.26 mmol) in CH₂Cl₂ (4 mL) at−78° C. was added BCl₃ (2 mL, 1M in CH₂Cl₂). The reaction mixture wasstirred at −78° C. for 1 h. The reaction was quenched at −78° C. bydropwise addition of TEA (2 mL) and MeOH (5 mL). The mixture was allowedto warm up to room temperature, evaporated, and co-evaporated with MeOHseveral times. The residue was treated with NaHCO₃ (1 g in 10 mL H₂O),concentrated and purified by HPLC to give the desired product Compound 5(48 mg, 60%). ¹H NMR (300 MHz, D₂O): δ 7.74 (s 1H), 6.76 (d, J=5 Hz,1H), 6.73 (d, J=5 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.8 (m, 2H), 0.84(s, 3H). MS=305.9 (M+H⁴). The other alpha-anomer was also obtained (9mg, 11%): ¹H NMR (300 MHz, D₂O): δ 7.70 (s 1H), 6.8 (d, J=5 Hz, 1H), 6.7(d, J=5 Hz, 1H), 4.25 (d, J=9 Hz, 1H), 4.07 (m, 1H), 3.85 (m, 1H), 3.7(m, 1H), 1.6 (s, 3H). MS=306.1 (M+H⁺).

Compound 6

To a solution of compound 5 (30 mg, 0.098 mmol) and 1H-tetrazole (30 mg,0.43 mmol) in anhydrous CH₃CN (1 mL) at 0° C. was added2,2-dimethyl-thiopropionic acidS-(2-{diisopropylamino-[2-(2,2-dimethyl-propionylsulfanyl)-ethoxy]-phosphanyloxy}-ethyl)ester (90 mg, 0.2 mmol) (described in J. Med. Chem., 1995, 3941). Thereaction mixture was stirred at 0° C. for 1 h, then H₂O₂ (30%, 80 uL)was added and stirred for 0.5 h at 0° C. The reaction was quenched withsodium thiosulfate (1 M, 1 mL) and NaHCO₃, diluted with CH₃CO₂Et. Theorganic phase was separated, washed with brine, dried over Na₂SO₄,filtered and concentrated. The residue was purified by HPLC to give thedesired Compound 6 (28 mg, 42%). ¹H NMR (300 MHz, CDCl₃): δ 8.04 (s,1H), 6.85 (d, J=4.5 Hz, 1H), 6.73 (d, J=4.5 Hz, 1H), 6.0 (brs, 2H), 4.6(m, 1H), 4.4 (m, 2H), 4.1 (m, 4H), 4.0 (d, J=4 Hz, 1H), 3.15 (m, 4H),1.24 (s, 18H), 0.99 (s, 3H). ³¹P NMR (300 MHz, CDCl₃): δ-1.825. MS=673.9(M+H⁺), 672.1 (M−H⁻).

General Procedure for Preparation of a Nucleoside Triphosphate:

To a pear-shaped flask (5-15 mL) is charged with a nucleoside (˜20 mg).Trimethyl phosphate (0.5-1.0 mL) is added. The solution is cooled withice-water bath. POCl₃ (40-45 mg) is added and stirred at 0° C. until thereaction is complete (1 to 4 h; the reaction progress is monitored byion-exchange HPLC; analytical samples are prepared by taking ˜3 uL ofthe reaction mixture and diluting it with 1.0 M Et₃NH₂CO₃ (30-50 uL)). Asolution of pyrophosphate-Bu₃N (250 mg) and Bu₃N (90-105 mg) inacetonitrile or DMF (1-1.5 mL) is then added. The mixture is stirred at0° C. for 0.3 to 2.5 h, and then the reaction is quenched with 1.0 MEt₃NH₂CO₃ (˜5 mL) The resulting mixture is stirred for additional 0.5-1h while warming up to room temperature. The mixture is concentrated todryness, re-dissolved in water (4 mL), and purified by ion exchangeHPLC. The fractions containing the desired product is concentrated todryness, dissolved in water (˜5 mL), concentrated to dryness, and againdissolved in water (˜5 mL). NaHCO₃ (30-50 mg) is added and concentratedto dryness. The residue is dissolved in water and concentrated todryness again. This process is repeated 2-5 times. The residue is thensubjected to C-18 HPLC purification, affording the desired product as asodium salt.

Compound 7

Compound 7 was prepared by the general method using Compound 5 asstarting material. ¹H NMR (300 MHz, D₂O): δ 7.76 (s, 1H), 6.95 (d, J=4.5Hz, 1H), 6.8 (d, J=4.5 Hz, 1H), 4.25 (m, 3H), 4.0 (d, J=6 Hz, 1H), 0.92(s, 3H). ³¹P NMR (300 MHz, D₂O): δ−5.6, −10.7, −21.4. MS=545.8 (M+Fr),544.0 (M−H⁻).

Compound 8

Compound 8 may be obtained from 2a in a manner similar to that describedin preparation of Compound 5 except using TMSN₃ instead of TMSCN.

Compound 9

Compound 9 may be obtained from 2a in a manner similar to that describedin preparation of Compound 5 except using TMS-acetylene instead ofTMSCN.

Compound 10

To a suspension of7-bromo-2,4-bis-methylsulfanyl-imidazo[2,1-f][1,2,4]triazine (preparedaccording to WO2008116064, 600 mg, 2.06 mmol) in anhydrous THF (6 mL)was dropwise added BuLi (1.6 M in hexanes, 1.75 mL, 2.81 mmol) at −78°C. The suspension became red brown solution after 5 min, and then 1f inTHF (0.6 mL) was added dropwise to the mixture. The mixture was thenallowed to warm up to room temperature. After 30 min, saturated NH₄Clwas added to quench the reaction. The mixture was diluted with ethylacetate; the organic layer was washed with brine and concentrated invacuo. The residue was purified by silica gel column chromatography(˜40% EtOAc/hexanes), affording 10a as an isomeric mixture (0.77 g,64%). MS=645.2 (M+H⁺).

Compound 10a (2.0 g, 3.10 mmol) was transferred to a steel bomb reactor,and cooled at −78° C. Liquid ammonia (˜20 mL) was collected at −78° C.and added to the bomb reactor. The bomb reactor was tightly sealed andwarmed up to room temperature. The mixture was then heated at 50° C. for20 h. Complete conversion occurred. After the gas was vented, theresidue was purified by silica gel column chromatography(EtOAc/hexanes), affording the product 10b as a pale yellow solid (1.78g, 94%). MS=614.3 (M+H⁺).

A solution of 10b (100 mg) in ethanol (about 10 ml) is treated withRaney Ni (about 500 mg) that is neutralized by washing with H₂O. Themixture is then heated to about 35 to about 80° C. until the reaction iscomplete. The catalyst is removed by filtration and the solution isconcentrated in vacuo. The residue is purified by chromatography to give10c.

Compound 10c may be treated with BBr₃ in a manner similar to thatdescribed in preparation of compound 2 to give Compound 10.

Compound 11

10a is treated with about one to ten mole equivalents of an alkali metalsalt of methanol in a suitable solvent such as dioxane for about one to48 hours. The mixture may also be heated from about 60 to about 110° C.for about one to 24 hours to complete the reaction. The mixture isneutralized with a strong acid and the intermediate is isolated byextraction and chromatography. The intermediate is dissolved in DCM andtreated with about two to about four mole equivalents of MCPBA for aboutone to about 24 hours. The mixture is treated with saturated NaHCO₃ andthe solution is extracted with EtOAc. The organic layer is washed withsaturated NaHCO₃ and brine and dried over MgSO₄. The solvent is removedin vacuo and the mixture is purified by chromatography to give 11a.

A solution of 11a in a suitable solvent such as methanol or THF istreated with about five to ten mole equivalents of NH₃ in methanol orTHF. The reaction is followed by TLC. After about one to 48 hours, thesolvent is evaporated and 11b is isolated by chromatography.Alternatively, the mixture of 11a and NH₃ is heated in a sealed glasstube or Parr bomb to about 60 to about 120° C. for about one to about 48hours and subsequently isolated in the same manner as described.

11b in DCM is cooled to about −78° C. and treated with about four to 10mole equivalents of BBr₃ for about one to about 24 hours. The mixture istreated with about 4:1 MeOH-pyridine and the solution was warmed to roomtemperature. The solvent is removed in vacuo and the mixture is treatedwith concentrated NH₄OH followed by removal of solvent (×3). The mixtureis purified by reverse phase HPLC to give 11.

Compound 12

Compound 12a (prepared according to J. Org. Chem., 1961, 26, 4605; 10.0g, 23.8 mmol) was dissolved in anhydrous DMSO (30 mL) and placed undernitrogen. Acetic anhydride (20 mL) was added, and the mixture wasstirred for 48 h at room temperature. When the reaction was complete byLC/MS, it was poured onto 500 mL ice water and stirred for 20 min. Theaqueous layer was extracted with ethyl acetate (3×200 mL). The organicextracts were combined and washed with water (3×200 mL). The aqueouslayers were discarded and the organic was dried over anhydrous MgSO₄ andevaporated to dryness. The residue was taken up in DCM and loaded onto asilica gel column. The final product 12b was purified by elution with25% EtOAc/hexanes; 96% yield. ¹H-NMR (CD₃CN): δ 3.63-3.75 (m, 2H), 4.27(d, 1H), 4.50-4.57 (m, 3H), 4.65 (s, 3H), 4.69-4.80 (m, 2H), 7.25 (d,2H), 7.39 (m, 13H).

7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (prepared according toWO2007056170, 0.5 g, 2.4 mmol) was suspended in anhydrous THF (10 mL).Under nitrogen with stirring, TMSCl (0.668 mL, 5.28 mml) was added andthe mixture was stirred for 20 min. at room temperature. The reactionwas then cooled to −78° C. and a solution of BuLi (6.0 mL, 1.6 N inhexanes) was added slowly. The reaction was stirred for 10 min. at −78°C. and then the lactone 12b was added via syringe. When the reaction wascomplete by LC/MS, acetic acid was added to quench. Solvents wereremoved by rotary evaporation and the residue was taken up in a mixtureof 50:50 dichloromethane/water (100 mL). The organic layer was collectedand washed with 50 mL additional water, dried over anhydrous MgSO₄ andfiltered. Evaporation and purification by column chromatography (0-50%EtOAc: hexanes) provided a 1:1 mixture of anomers 12c; 25% yield. LC/MS(m/z: 553, M+H⁺).

Compound 12c (0.4 g, 0.725 mmol) was stirred in a 1:1 mixture of aceticacid and methanol (10 mL) for 12 h. When the reaction was complete byLC/MS, solvents were removed by high vacuum. The residue was taken up indichloromethane and loaded onto a silica gel column. A mixture ofanomers was eluted using a gradient of 0-75% ethyl acetate and hexanes;51.4% yield of compound 12d. ¹H-NMR (CD₃CN): δ 2.87 (s, 3H), 3.58-3.79(dd, 2H), 4.11-4.19 (m, 1H), 4.23-4.33 (m, 1H), 4.39-4.42 (m, 1H),4.49-4.60 (m, 3H), 4.68-4.73 (m, 2H), 6.22 (bs, 2H), 6.72 (d, 2H), 6.79(d, 1H), 6.84 (d, 1H), 7.17 (m, 2H), 7.39 (m, 13H), 7.84 (s, 1H).

Compound 12d (0.150 g, 0.265 mmol) was dissolved in a 1:1 mixture ofmethanol and acetic acid (20 mL). 10% Pd/C (150 mg) was added and thereaction was flushed with nitrogen three times. With stirring, hydrogengas was introduced. The reaction was stirred under hydrogen for 16 h.When the reaction was complete by LC/MS, the catalyst was filtered offand solvents removed under vacuum. The residue was re-dissolved in amixture of water and TEA (to keep pH at ˜10), and both anomers werepurified by prep HPLC under neutral conditions; a total of 51% yield.¹H-NMR of compound 12 (D₂O): δ 3.16 (s, 3H), 3.69-3.84 (dd, 2H),4.07-4.10 (m, 1H), 4.22-4.24 (m, 1H), 6.74 (d, 1H), 6.78 (d, 1H), 7.70(s, 1H). ¹H-NMR of the other alpha-anomer (D₂O): δ 2.87 (s, 3H),3.58-3.84 (dd, 2H), 3.99-4.09 (m 1H), 4.30-4.38 (m, 1H), 4.49 (d, 1H),6.75 (d, 1H), 6.82 (d, 1H), 7.69 (s, 1H).

Compound 13

Compound 12c (0.28 g, 0.51 mmol) was dissolved in anhydrousdichloromethane and placed under nitrogen. Trimethylsilyl cyanide (0.35mL) was added and the mixture was cooled to 0° C. After stirring for 10min., boron trifluoride etherate (50 ul) was added and the reaction wasallowed to warm to room temperature. When the reaction was complete byLC/MS, triethylamine was added to quench and solvents were removed byrotary evaporation. The residue was taken up in dichloromethane andloaded onto a silica gel column. A mixture of anomers was eluted using agradient of 0-75% ethyl acetate and hexanes; 37% yield of 13a. ¹H-NMR(CD₃CN): δ 3.61-3.90 (m, 2H), 4.09-4.19 (m, 2H), 4.30-4.88 (m, 7H), 4.96(d, 0.5H), 5.10 (d, 0.5H), 6.41 (bs, 2H), 6.73-6.78 (m, 1H), 6.81-6.88(m, 1H), 7.17 (m, 2H), 7.39 (m, 13H), 7.86 (s, 0.5H), 7.93 (s, 0.5H).

Compound 13a (0.70 mg, 0.124 mmol) was dissolved in anhydrousdichloromethane (2 ml), placed under nitrogen, and cooled to −78° C. Asolution of 1 N boron trichloride in dichloromethane (0.506 ml) wasadded and the reaction stirred for 1 h at −78° C. When the reaction wascomplete by LC/MS, methanol was added to quench. The reaction wasallowed to rise to room temperature and solvents were removed by rotaryevaporation. The product anomers were purified by prep-HPLC; a total of74% yield. ¹H-NMR of Compound 13 (D₂O): δ 3.65-3.75 (dd, 2H), 4.12 (t,1H), 4.29 (q, 1H), 4.80 (d, 1H), 6.97 (d, 1H), 7.14 (d, 1H), 7.93 (s,1H). ¹H-NMR of the other alpha-anomer (D₂O): δ 3.72-3.93 (dd, 2H),4.16-4.19 (m, 1H), 4.60-4.62 (m 1H), 5.01 (d, 1H), 6.95 (d, 1H), 7.28(d, 1H) 7.96 (s, 1H).

Compound 14

Compound 14 may be obtained from 12c in a manner similar to the methodused to synthesize Compound 4.

Compound 15

Compound 15 may be obtained from 12c in a manner similar to thatdescribed in preparation of Compound 13 except using TMSN₃ instead ofTMSCN.

Compound 16

Compound 16 may be obtained from 12c in a manner similar to thatdescribed in preparation of Compound 13 except using TMS-acetyleneinstead of TMSCN.

Compound 17

A mixture of about 0.05 mmol of Compound 5 and about 0.5 mL oftrimethylphosphate is sealed in a container for about one to about 48hours. The mixture is cooled to about −10 to about 10° C. and about0.075 mmol of phosphorous oxychloride is added. After about one to about24 hours, the reaction is quenched with about 0.5 mL of 1Mtetraethylammonium bicarbonate and the desired fraction are isolated byanion exchange chromatography. The appropriate fractions are thendesalted by reverse-phase chromatography to give Compound 17.

Compound 18

Compound 17 (about 1.19 mmol) is dried over phosphorous pentoxide in avacuum for about overnight. The dried material is suspended in about 4mL of anhydrous DMF and about 4.92 mmol DIPEA. About 7.34 mmol ofiso-propyl chloromethyl carbonate (Antiviral Chemistry & Chemotherapy8:557 (1997)) is added and the mixture is heated to about 25 to about60° C. for about 30 min to about 24 hours. Heating is removed for aboutone to about 48 hours and the reaction filtered. The filtrate is dilutedwith water, Compound 18 is partitioned into CH₂Cl₂, the organic solutionis dried and evaporated, and the residue is purified by reverse-phaseHPLC to isolate Compound 18.

Mono Phosphoramidate Prodrugs

Non-limiting examples of mono-phosphoramidate prodrugs comprising theinstant invention may be prepared according to general Scheme 1.

The general procedure comprises the reaction of an amino acid ester salt19b, e.g., HCl salt, with an aryl dichlorophosphate 19a in the presenceof about two to ten equivalents of a suitable base to give thephosphoramidate 19c. Suitable bases include, but are not limited to,imidazoles, pyridines such as lutidine and DMAP, tertiary amines such astriethylamine and DABCO, and substituted amidines such as DBN and DBU.Tertiary amines are particularly preferred. Preferably, the product ofeach step is used directly in the subsequent steps withoutrecrystallization or chromatography. Specific, but non-limiting,examples of 19a, 19b, and 19c can be found in WO 2006/121820 that ishereby incorporated by reference in its entirety. A nucleoside base 19dreacts with the phosphoramidate 19c in the presence of a suitable base.Suitable bases include, but are not limited to, imidazoles, pyridinessuch as lutidine and DMAP, tertiary amines such as triethylamine andDABCO, and substituted amidines such as DBN and DBU. The product 19e maybe isolated by recrystallization and/or chromatography.

Compound 20

About 3.1 mmol of phenyl methoxyalaninyl phosphorochloridate (preparedaccording to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) in about3 mL of THF is added to a mixture of about 0.5 mmol of Compound 11 andabout 3.8 mmol of N-methylimidazole in about 3 mL THF. The reaction isstirred for about 24 hours and the solvent is removed under reducedpressure. The residue is purified by reverse-phase HPLC to give Compound20.

Compound 21

About 3.1 mmol of 4-chlorophenyl 2-propyloxyalaninyl phosphorochloridate(prepared according to McGuigan et al, J. Med. Chem. 1993, 36,1048-1052) in about 3 mL of THF is added to a mixture of about 0.5 mmolof Compound 5 and about 3.8 mmol of N-methylimidazole in about 3 mL THF.The reaction is stirred for about 24 hours and the solvent is removedunder reduced pressure. The residue is purified by reverse-phase HPLC togive Compound 21.

Compound 22

A mixture of about 0.52 mmol of Compound 13 and about 12 mL dry acetone,about 0.7 mL of 2,2,-dimethoxypropane and about 1.28 mmol ofdi-p-nitrophenylphosphoric acid is stirred for about 24 hours to aboutseven days. The reaction mixture is neutralized with about 20 mL of 0.1N NaHCO₃ and the acetone is evaporated. The desired material ispartitioned into chloroform, the chloroform solution is dried, and thesolvent is evaporated. Compound 22 is purified from the residue byconventional means.

Compound 23

A solution of about 0.53 mmol of Compound 22 in about 5 mL of DMF istreated with about 1 mL of a 1 M solution of t-butylmagnesium chloridein THF. After about 30 min to about 5 hours, a solution of about 0.65mmol oftrans-4-[(S)-pyridin-4-yl]-2-(4-nitrophenoxy)-2-oxo-1,3,2-dioxaphosphorinane(Reddy, Tetrahedron Letters 2005, 4321-4324) is added and the reactionis stirred for about one to about 24 hours. The solution is concentratedin a vacuum and the residue is purified by chromatography to giveCompound 23.

Compound 24

A solution of about 70% aqueous trifluoroacetic acid is cooled to 0° C.and is treated with about 0.32 mmol of Compound 23 for about one to 24hours. The solution is concentrated and the residue is purified bychromatography to give Compound 24.

Compound 25

A solution of about 1.56 mmol of Compound 24 in about 15 mL of THF istreated with about 4.32 mmol of CDI. After about one to about 24 hours,the solvent is evaporated and the residue is purified by chromatographyto give Compound 25.

Compound 26

About 3.1 mmol of 4-chlorophenyl 2-ethoxyalaninyl phosphorochloridate(prepared according to McGuigan et al, J. Med. Chem. 1993, 36,1048-1052) in about 3 mL of THF is added to a mixture of about 0.5 mmolof Compound 4 and about 3.8 mmol of N-methylimidazole in about 3 mL THF.The reaction is stirred for about 24 hours and the solvent is removedunder reduced pressure. The residue is purified by reverse-phase HPLC togive Compound 26.

Compound 27

A solution of Compound 26 in DMSO is treated with about 3 moleequivalents of potassium t-butoxide for about 15 min to 24 hours. Thereaction is quenched with 1N HCl and Compound 27 is isolated byreverse-phase HPLC.

Compound 28

Compound 28 is prepared in the same manner as Compound 5 but usingCompound 10c as a starting material.

Compound 29

Compound 29 is prepared in the same manner as Compound 17 using Compound28 as a starting material.

Compound 30

Compound 30 is prepared by treating Compound 29 with about one to aboutfive equivalents of DCC in pyridine and heating the reaction to refluxfor about one to about 24 hours. Compound 30 is isolated by conventionalion exchange and reverse-phase HPLC.

Compound 31

A solution of about 0.4 mmol of Compound 30 in about 10 mL of DMF istreated with about 0.8 mmol of DIPEA and about 0.8 mmol of chloromethylisopropyl carbonate (WO2007/027248). The reaction is heated to about 25to about 80° C. for about 15 min to about 24 hours. The solvent isremoved under vacuum and the residue is purified by HPLC to giveCompound 31.

Compound 32

Compound 10b is dissolved in DCM and treated with about two to aboutfour mole equivalents of MCPBA for about one to about 24 hours. Themixture is treated with saturated NaHCO₃ and the solution is extractedwith EtOAc. The organic layer is washed with saturated NaHCO₃ and brineand dried over MgSO₄. The solvent is removed in vacuo and the mixture ispurified by chromatography to give 32a. Compound 32a is transferred to asteel bomb reactor, and is cooled at −78° C. Liquid ammonia is collectedat −78° C. and is added to the bomb reactor. The bomb reactor is tightlysealed and is warmed up to room temperature. The mixture is heated atabout 50° C. for about 24 h. The gas is vented and 32b is isolated bychromatography. Compound 32b is converted to Compound 32 in the samemanner as for the conversion of Compound 2a to Compound 2.

Compound 33

Compound 32b is converted to Compound 33 in the same manner as theconversion of Compound 2a to Compound 5.

Compound 34

Compound 33 (about 0.22 mmol) is dissolved in anhydrous pyridine (about2 mL) and chlorotrimethylsilane (about 0.17 mL) is added. The mixture isstirred at about 0 to about 25° C. for about one to about 24 hours.Additional chlorotrimethylsilane (about 0.1 mL) is added and thereaction is stirred for about one to about 24 hours.4,4′-Dimethoxytrityl chloride (about 0.66 mmol) and DMAP (about 0.11 toabout 0.22 mmol) is sequentially added. The mixture is stirred for aboutone to about 24 hours. A solution of TBAF (1.0 M, about 0.22 mL) in THFis added and the reaction is stirred for about one to about 24 hours.The mixture is partitioned between ethyl acetate and water. The ethylacetate layer is dried and concentrated. The residue is purifiedchromatography to afford Compound 34 which may be a mixture of mono- anddi-dimethoxytritylated compounds.

Compound 35

A mixture of about 1.25 mmol of Compound 34 and about 1.9 mmol oftriethylammonium 2-(2,2-dimethyl-3-(trityloxy)propanoylthio)ethylphosphonate (WO2008082601) is dissolved in anhydrous pyridine (about 19mL). Pivaloyl chloride (about 2.5 mmol) is added dropwise at about −30to about 0° C. and the solution is stirred at for about 30 min to about24 hours. The reaction is diluted with methylene chloride and isneutralized with aqueous ammonium chloride (about 0.5M). The methylenechloride phase is evaporated and the residue is dried and is purified bychromatography to give Compound 35 which may be a mixture of mono- anddi-dimethoxytritylated compounds.

Compound 36

To a solution of about 0.49 mmol of Compound 35 in anhydrous carbontetrachloride (about 5 mL) is added dropwise benzylamine (about 2.45mmol). The reaction mixture is stirred for about one to about 24 hours.The solvent is evaporated and the residue is purified by chromatographyto give Compound 36 which may be a mixture of mono- anddi-dimethoxytritylated compounds.

Compound 37

A solution of about 2 mmol of Compound 36 in methylene chloride (about10 mL) is treated with an aqueous solution of trifluoroacetic acid (90%,about 10 mL). The reaction mixture is stirred at about 25 to about 60°C. for about one to about 24 hours. The reaction mixture is diluted withethanol, the volatiles are evaporated and the residue is purified bychromatography to give Compound 37.

Compound 38

About 90 mM Compound 14 in THF is cooled to about −78° C. and about 2.2to about 4.4 equivalents of t-butylmagneisum chloride (about 1 M in THF)is added. The mixture is warmed to about 0° C. for about 30 mM and isagain cooled to about −78° C. A solution of(2S)-2-{[chloro(1-phenoxy)phosphoryl]amino}propyl pivaloate(WO2008085508) (1 M in THF, about 2 equivalents) is added dropwise. Thecooling is removed and the reaction is stirred for about one to about 24hours. The reaction is quenched with water and the mixture is extractedwith ethyl acetate. The extracts are dried and evaporated and theresidue purified by chromatography to give Compound 38.

Compound 39

A solution of about one part Compound 39a (Patil, et al.; Journal ofHeterocyclic Chemistry 1994, 31(4), 781-6) in anhydrous DMF is cooled toabout −20° C. and about 0.5 parts of 1,3-diromo-5,5-dimethylhydantoin isadded in portions. After about one to about 24 hours, a saturate aqueoussodium bisulfate solution is added and the solids are collected byfiltration. The solids are partitioned between ethyl acetate and diluteaqueous sodium carbonate. The organic phase is washed with dilute sodiumcarbonate then dried and concentrated to give Compound 39.

Compound 40

A solution of about one part of 39 and about four parts oftrimethylsilylchloride in THF is stirred at about 20 to about 60° C. forabout 30 min to about six hours. The solution is cooled to about −70 toabout −100° C. and a solution of about five parts of butyllithium inhexanes is added. After about 30 min. to about three hours, the reactionis allowed to warm to about 0° C. over about three hours. The reactionis quenched with saturated NaHCO₃ and the mixture is extracted withether. The ether extracts are washed with brine, dried, and the solventevaporated to give 40a which may be further purified by chromatography.

A solution of one part of 40a in dichloromethane is cooled to about −100to about −70° C. A 1.0 M solution of BCl₃ in dichloromethane (about 10to 20 parts) is added and the reaction is stirred for about 30 min. toabout 3 hours. A mixture of pyridine and methanol (about 1:2) is thenadded to quench the reaction. The resulting mixture is slowly warmed toroom temperature and concentrated. The residue is suspended in about 27%ammonium hydroxide and concentrated. This process is repeated twice. Theresidue is re-dissolved in methanol and concentrated. This process isrepeated once. The residue is purified by RP-HPLC to give 40.

Compound 41

Compound 41 may be prepared from Compound 40a in the same manner asCompound 5 was prepared from Compound 2a.

Compound 42

A solution of about one part Compound 42a (Patil, et al.; Journal ofHeterocyclic Chemistry 1994, 31(4), 781-6) in anhydrous DMF is cooled toabout −20° C. and about 0.5 parts of 1,3-diromo-5,5-dimethylhydantoin isadded in portions. After about one to about 24 hours, a saturate aqueoussodium bisulfite solution is added and the solids are collected byfiltration. The solids are partitioned between ethyl acetate and diluteaqueous sodium carbonate. The organic phase is washed with dilute sodiumcarbonate then dried and concentrated to give Compound 42b.

A solution of about one part of 42b and about four parts oftrimethylsilylchloride in THF is stirred at about 20 to about 60° C. forabout 30 min to about six hours. The solution is cooled to about −70 toabout −100° C. and a solution of about five parts of butyllithium inhexanes is added. After about 30 min. to about three hours, the reactionis allowed to warm to about 0° C. over about three hours. The reactionis quenched with saturated NaHCO₃ and the mixture is extracted withether. The ether extracts are washed with brine, dried, and the solventevaporated to give 42c which may be further purified by chromatography.

Compound 42 may be prepared from Compound 42a in the same manner asCompound 5 was prepared from Compound 2a.

Compound 43

A solution of one part of Compound 2a in CH₂Cl₂ is treated with abouttwo parts of BF₃OEt₂ at about −78° C. under an argon atmosphere andabout three parts of (CH₂═CH—)₂SnBu₂. The reaction temperature isgradually raised to rt during about one to four hours. Usual extractiveworkup followed by purification by chromatography will give Compound43a. Compound 43a is dissolved in methanol and dichloromethane andcooled to about −78° C. Ozone is bubbled into the stirred solution forabout 1.5 hours at −78° C. The solution is then flushed with nitrogen toremove the ozone. Sodium borohydride (about 8 equivalents) is then addedin small portions over about 5 minutes at −78° C. Methanol is added andthe reaction is slowly warmed to about 0° C. After about 1.5 hours, thereaction is quenched with saturated bicarbonate solution and extractedwith CH₂Cl₂. The combined organics are washed with brine, dried,filtered and the solvent is removed in vacuo. The residue is purified bychromatography to give Compound 43b. Compound 43b may be debenzylated inthe same manner as Compound 2a to give Compound 43 that may be furtherpurified by chromatography.

Compound 44

Compound 44 may be obtained in the same manner as Compound 43, startingwith Compound 12c.

Antiviral Activity

Another aspect of the invention relates to methods of inhibiting viralinfections, comprising the step of treating a sample or subjectsuspected of needing such inhibition with a composition of theinvention.

Within the context of the invention samples suspected of containing avirus include natural or man-made materials such as living organisms;tissue or cell cultures; biological samples such as biological materialsamples (blood, serum, urine, cerebrospinal fluid, tears, sputum,saliva, tissue samples, and the like); laboratory samples; food, water,or air samples; bioproduct samples such as extracts of cells,particularly recombinant cells synthesizing a desired glycoprotein; andthe like. Typically the sample will be suspected of containing anorganism which induces a viral infection, frequently a pathogenicorganism such as a tumor virus. Samples can be contained in any mediumincluding water and organic solvent\water mixtures. Samples includeliving organisms such as humans, and man made materials such as cellcultures.

If desired, the anti-virus activity of a compound of the invention afterapplication of the composition can be observed by any method includingdirect and indirect methods of detecting such activity. Quantitative,qualitative, and semiquantitative methods of determining such activityare all contemplated. Typically one of the screening methods describedabove are applied, however, any other method such as observation of thephysiological properties of a living organism are also applicable.

The antiviral activity of a compound of the invention can be measuredusing standard screening protocols that are known. For example, theantiviral activity of a compound can be measured using the followinggeneral protocols.

Cell-Based Flavivirus Immunodetection Assay

BHK21 or A549 cells are trypsinized, counted and diluted to 2×10⁵cells/mL in Hams F-12 media (A549 cells) or RPMI-1640 media (BHK21cells) supplemented with 2% fetal bovine serum (FBS) and 1%penicillin/streptomycin. 2×10⁴ cells are dispensed in a clear 96-welltissue culture plates per well and placed at 37° C., 5% CO₂ overnight.On the next day, the cells are infected with viruses at multiplicity ofinfection (MOI) of 0.3 in the presence of varied concentrations of testcompounds for 1 hour at 37° C. and 5% CO₂ for another 48 hours. Thecells are washed once with PBS and fixed with cold methanol for 10 min.After washing twice with PBS, the fixed cells are blocked with PBScontaining 1% FBS and 0.05% Tween-20 for 1 hour at room temperature. Theprimary antibody solution (4G2) is then added at a concentration of 1:20to 1:100 in PBS containing 1% FBS and 0.05% Tween-20 for 3 hours. Thecells are then washed three times with PBS followed by one hourincubation with horseradish peroxidase(HRP)-conjugated anti-mouse IgG(Sigma, 1:2000 dilution). After washing three times with PBS, 50microliters of 3,3′,5,5′-tetramethylbenzidine (TMB) substrate solution(Sigma) is added to each well for two minutes. The reaction is stoppedby addition of 0.5 M sulfuric acid. The plates are read at 450 nmabsorbance for viral load quantification. After measurement, the cellsare washed three times with PBS followed by incubation with propidiumiodide for 5 min. The plate is read in a Tecan Safire™ reader(excitation 537 nm, emission 617 nm) for cell number quantification.Dose response curves are plotted from the mean absorbance versus the logof the of the concentration of test compounds. The EC₅₀ is calculated bynon-linear regression analysis. A positive control such asN-nonyl-deoxynojirimycin may be used.

Cell-Based Flavivirus Cytopathic Effect Assay

For testing against West Nile virus or Japanese encephalitis virus,BHK21 cells are trypsinized and diluted to a concentration of 4×10⁵cells/mL in RPMI-1640 media supplemented with 2% FBS and 1%penicillin/streptomycin. For testing against dengue virus, Huh7 cellsare trypsinized and diluted to a concentration of 4×10⁵ cells/mL in DMEMmedia supplemented with 5% FBS and 1% penicillin/streptomycin. A 50microliter of cell suspension (2×10⁴ cells) is dispensed per well in a96-well optical bottom PIT polymer-based plates (Nunc). Cells are grownovernight in culture medium at 37° C., 5% CO₂, and then infected withWest Nile virus (e.g. B956 strain) or Japanese encephalitis virus (e.g.Nakayama strain) at MOI=0.3, or with dengue virus (e.g. DEN-2 NGCstrain) at MOI=1, in the presence of different concentrations of testcompounds. The plates containing the virus and the compounds are furtherincubated at 37° C., 5% CO₂ for 72 hours. At the end of incubation, 100microliters of CellTiter-Glo™ reagent is added into each well. Contentsare mixed for 2 minutes on an orbital shaker to induce cell lysis. Theplates are incubated at room temperature for 10 minutes to stabilizeluminescent signal. Luminescence reading is recorded using a platereader. A positive control such as N-nonyl-deoxynojirimycin may be used.

Antiviral Activity in a Mouse Model of Dengue Infection.

Compounds are tested in vivo in a mouse model of dengue virus infection(Schul et al. J. Infectious Dis. 2007; 195:665-74). Six to ten week oldAG129 mice (B&K Universal Ltd, Hll, UK) are housed in individuallyventilated cages. Mice are injected intraperitoneally with 0.4 mL TSV01dengue virus 2 suspension. Blood samples are taken by retro orbitalpuncture under isoflurane anaesthesia. Blood samples are collected intubes containing sodium citrate to a final concentration of 0.4%, andimmediately centrifuged for 3 minutes at 6000 g to obtain plasma. Plasma(20 microliters) is diluted in 780 microliters RPMI-1640 medium and snapfrozen in liquid nitrogen for plaque assay analysis. The remainingplasma is reserved for cytokine and NS1 protein level determination.Mice develop dengue viremia rising over several days, peaking on day 3post-infection.

For testing of antiviral activity, a compound of the invention isdissolved in vehicle fluid, e.g. 10% ethanol, 30% PEG 300 and 60% D5W(5% dextrose in water; or 6N HCl (1.5 eq):1N NaOH (pH adjusted to 3.5):100 mM citrate buffer pH 3.5 (0.9% v/v:2.5% v/v: 96.6% v/v). Thirty six6-10 week old AG129 mice are divided into six groups of six mice each.All mice are infected with dengue virus as described above (day 0).Group 1 is dosed by oral gavage of 200 mL/mouse with 0.2 mg/kg of acompound of the invention twice a day (once early in the morning andonce late in the afternoon) for three consecutive days starting on day 0(first dose just before dengue infection). Groups 2, 3 and 4 are dosedthe same way with 1 mg/kg, 5 mg/kg and 25 mg/kg of the compound,respectively. A positive control may be used, such as(2R,3R,4R,5R)-2-(2-amino-6-hydroxy-purin-9-yl)-S-hydroxymethyl-3-methyl-tetrahydro-furan-3,4-diol,dosed by oral gavage of 200 microliters/mouse the same way as theprevious groups. A further group is treated with only vehicle fluid.

On day 3 post-infection approximately 100 microliter blood samples(anti-coagulated with sodium citrate) are taken from the mice byretro-orbital puncture under isoflurane anaesthesia. Plasma is obtainedfrom each blood sample by centrifugation and snap frozen in liquidnitrogen for plague assay analysis. The collected plasma samples areanalyzed by plague assay as described in Schul et al. Cytokines are alsoanalysed as described by Schul. NS1 protein levels are analysed using aPlatelia™ kit (BioRad Laboratories). An anti-viral effect is indicatedby a reduction in cytokine levels and/or NS1 protein levels.

Typically, reductions in viremia of about 5-100 fold, more typically10-60 fold, most typically 20-30 fold, are obtained with 5-50 mg/kg biddosages of the compounds of the invention.

HCV IC₅₀ Determination

Assay Protocol: NS5b polymerase assay (40 μL) was assembled by adding 28μL polymerase mixture (final concentration: 50 mM Tris-HCl at pH 7.5, 10mM KCL, 5 mM MgCl₂, 1 mM DTT, 10 mM EDTA, 4 ng/μL of RNA template, and75 nM HCV Δ21 NS5b polymerase) to assay plates followed by 4 μL ofcompound dilution. The polymerase and compound were pre-incubated at 35°C. for 10 minute before the addition of 8 μL of nucleotide substratemixture (33P-α-labeled competing nucleotide at K_(M) and 0.5 mM of theremaining three nucleotides). The assay plates were covered andincubated at 35° C. for 90 min. Reactions were then filtered through96-well DEAE-81 filter plates via vacuum. The filter plates were thenwashed under vacuum with multiple volumes of 0.125 M NaHPO₄, water, andethanol to remove unincorporated label. Plates were then counted onTopCount to assess the level of product synthesis over backgroundcontrols. The IC50 value is determined using Prism fitting program.

Preferably, compounds described herein inhibited NS5b polymerase with anIC₅₀'s below 1000 μM, more preferably below 100 μM, and most preferablybelow 10 μM. For example, compound 17 has an IC₅₀ below 1 μM.

HCV EC₅₀ Determination

Replicon cells were seeded in 96-well plates at a density of 8×10³ cellsper well in 100 μL of culture medium, excluding Geneticin. Compound wasserially diluted in 100% DMSO and then added to the cells at a 1:200dilution, achieving a final concentration of 0.5% DMSO and a totalvolume of 200 μl. Plates were incubated at 37° C. for 3 days, afterwhich culture medium was removed and cells were lysed in lysis bufferprovided by Promega's luciferase assay system. Following themanufacturer's instruction, 100 μL of luciferase substrate was added tothe lysed cells and luciferase activity was measured in a TopCountluminometer. Preferably, compounds described herein have EC50's below1000 μM, more preferably below 100 μM, and most preferably below 10 μM.

Representative examples of the activity of the compounds Formula I-IIIare shown in the Table below wherein A represents an EC₅₀ below 1 μM, Brepresents an EC₅₀ between 1 and 10 μM, and C represents an EC₅₀ between10 and 100 μM.

Example No. EC₅₀, μM 2 C 3 C 4 C 5 C 6 A 12 B 13 B

The cytotoxicity of a compound of the invention can be determined usingthe following general protocol.

Cytotoxicity Cell Culture Assay (Determination of CC50):

The assay is based on the evaluation of cytotoxic effect of testedcompounds using a metabolic substrate.

Assay Protocol for Determination of CC50:

-   1. Maintain MT-2 cells in RPMI-1640 medium supplemented with 5%    fetal bovine serum and antibiotics.-   2. Distribute the cells into a 96-well plate (20,000 cell in 100 μl    media per well) and add various concentrations of the tested    compound in triplicate (100 μl/well). Include untreated control.-   3. Incubate the cells for 5 days at 37° C.-   4. Prepare XTT solution (6 ml per assay plate) in dark at a    concentration of 2 mg/ml in a phosphate-buffered saline pH 7.4. Heat    the solution in a water-bath at 55° C. for 5 min. Add 50 μl of    N-methylphenazonium methasulfate (5 μg/ml) per 6 ml of XTT solution.-   5. Remove 100 μl media from each well on the assay plate and add 100    μl of the XTT substrate solution per well. Incubate at 37° C. for 45    to 60 min in a CO₂ incubator.-   6. Add 20 μl of 2% Triton X-100 per well to stop the metabolic    conversion of XTT.-   7. Read the absorbance at 450 nm with subtracting off the background    at 650 nm.-   8. Plot the percentage absorbance relative to untreated control and    estimate the CC50 value as drug concentration resulting in a 50%    inhibition of the cell growth. Consider the absorbance being    directly proportional to the cell growth.

All publications, patents, and patent documents cited herein above areincorporated by reference herein, as though individually incorporated byreference.

The invention has been described with reference to various specific andpreferred embodiments and techniques. However, one skilled in the artwill understand that many variations and modifications may be made whileremaining within the spirit and scope of the invention.

1. A compound of Formula I:

or a pharmaceutically acceptable salt, thereof; wherein: each R¹, R²,R³, R⁴, or R⁵ is independently H, OR^(a), N(R^(a))₂, N₃, CN, NO₂,S(O)_(n)R^(a), halogen, (C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, (C₁-C₈)substituted alkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl,(C₂-C₈)alkynyl, (C₂-C₈) substituted alkynyl, or aryl(C₁-C₈)alkyl; or anytwo R¹, R², R³, R⁴, or R⁵ on adjacent carbon atoms when taken togetherare —O(CO)O— or when taken together with the ring carbon atoms to whichthey are attached form a double bond; R⁶ is CN; each n is independently0, 1, or 2; each R^(a) is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl,(C₂-C₈)alkynyl, aryl(C₁-C₈)alkyl, (C₄-C₈)carbocyclylalkyl, —C(═O)R¹¹,—C(═O)OR¹¹, —C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), or —SO₂NR¹¹R¹²; R⁷ is H, —C(═O)R¹¹, —C(═O)OR¹¹,—C(═O)NR¹¹R¹², —C(═O)SR¹¹, —S(O)R¹¹, —S(O)₂R¹¹, —S(O)(OR¹¹),—S(O)₂(OR¹¹), —SO₂NR¹¹R¹², or

Y is O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or N—NR₂; W¹ and W², whentaken together, are —Y³(C(R^(y))₂)₃Y³—; or one of W¹ or W² together witheither R³ or R⁴ is —Y³— and the other of W¹ or W² is Formula Ia; or W¹and W² are each, independently, a group of the Formula Ia:

wherein: each Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR),⁺N(O)(OR), or N—NR₂; each Y² is independently a bond, O, CR₂, NR,⁺N(O)(R), N(OR), ⁺N(O)(OR), N—NR₂, S, S—S, S(O), or S(O)₂; each Y³ isindependently O, S, or NR; M2 is 0, 1 or 2; each R^(x) is a group of theformula:

wherein: each M1a, M1c, and M1d is independently 0 or 1; M12c is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; each R⁷ is independently H, F, Cl,Br, I, OH, —CN, —N₃, —NO₂, —OR, —C(═Y¹)R, —C(Y¹)W⁵, —C(═Y¹)OR,—C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R, —S(O)₂R, —SO₂W⁵, —S(O)(OR),—S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂), —SC(═Y¹)R,—SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR,—N(R)C(═Y¹)N(R)₂, —SO₂NR₂, W⁵, (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈)substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ substituted heterocyclyl, arylalkyl or substitutedarylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl, heterocyclyl, orarylalkyl is independently optionally substituted with one or more Zgroups; or when taken together, two R^(y) on the same carbon atom form acarbocyclic ring of 3 to 7 carbon atoms; each W⁵ is independently acarbocycle or a heterocycle optionally substituted with 1 to 3 R^(z)groups; each R^(z) is independently F, Cl, Br, I, OH, —CN, —N₃, —NO₂,—OR, —C(═Y¹)R, —C(═Y¹)OR, —C(═Y¹)N(R)₂, —N(R)₂, —⁺N(R)₃, —SR, —S(O)R,—S(O)₂R, —S(O)(OR), —S(O)₂(OR), —OC(═Y¹)R, —OC(═Y¹)OR, —OC(═Y¹)(N(R)₂),—SC(═Y¹)R, —SC(═Y¹)OR, —SC(═Y¹)(N(R)₂), —N(R)C(═Y¹)R, —N(R)C(═Y¹)OR,—N(R)C(═Y¹)N(R)₂, —SO₂NR₂, (C₁-C₈) alkyl, (C₁-C₈) substituted alkyl,(C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈)substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl, C₂-C₂₀heterocyclyl, C₂-C₂₀ substituted heterocyclyl, arylalkyl or substitutedarylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl, heterocyclyl, orarylalkyl is independently optionally substituted with one or more Zgroups; each R is independently H, (C₁-C₈) alkyl, (C₁-C₈) substitutedalkyl, (C₂-C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl,(C₂-C₈) substituted alkynyl, C₆-C₂₀ aryl, C₆-C₂₀ substituted aryl,C₂-C₂₀ heterocyclyl, C₂-C₂₀ substituted heterocyclyl, arylalkyl orsubstituted arylalkyl; wherein each alkyl, alkenyl, alkynyl, aryl,heterocyclyl, or arylalkyl is independently optionally substituted withone or more Z groups; each X¹ or X² is independently C—R¹⁰ or N; each R⁸is halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN,—CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹²,C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl,aryl(C₁-C₈)alkyl, OR¹¹ or SR¹¹; wherein each aryl or heteroaryl isindependently optionally substituted with one or more Z groups; each R⁹or R¹⁰ is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹²,N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂,—C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹ or SR¹¹; each R¹¹ orR¹² is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl,(C₄-C₈)carbocyclylalkyl, optionally substituted aryl, optionallysubstituted heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_(n)(C₁-C₈)alkyl oraryl(C₁-C₈)alkyl; wherein each aryl or heteroaryl is independentlyoptionally substituted with one or more Z groups; or R¹¹ and R¹² takentogether with a nitrogen to which they are both attached form a 3 to 7membered heterocyclic ring wherein any one carbon atom of saidheterocyclic ring can optionally be replaced with —O—, —S— or —NR^(a)—;each Z is independently halogen, —O⁻, ═O, —OR^(b), —SR^(b), —S⁻, —NR^(b)₂, —N⁺R^(b) ₃, ═NR^(b), —CN, —OCN, —SCN, —N═C═O, —NCS, —NO, —NO₂, ═N₂,—N₃, —NHC(═O)R^(b), —OC(═O)R^(b), —NHC(═O)NR^(b) ₂, —S(═O)₂—, —S(═O)₂OH,—S(═O)₂R^(b), —OS(═O)₂OR^(b), —S(═O)₂NR^(b) ₂, —S(═O)R^(b),—OP(═O)(OR^(b))₂, —P(═O)(OR^(b))₂, —P(═O)(O⁻)₂, —P(═O)(OH)₂,—P(O)(OR^(b))(O⁻), —C(═O)R^(b), —C(═O)X, —C(S)R^(b), —C(O)OR^(b),—C(O)O⁻, —C(S)OR^(b), —C(O)SR^(b), —C(S)SR^(b), —C(O)NR^(b) ₂,—C(S)NR^(b) ₂, —C(═NR^(b))NR^(b) ₂, where each R^(b) is independently H,alkyl, aryl, arylalkyl, or heterocycle; wherein each (C₁-C₈)alkyl,(C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl of each R¹, R², R³,R⁴, or R⁵, R⁶ is, independently, optionally substituted with one or morehalo, hydroxy, CN, N₃, N(R^(a))₂ or OR^(a); and wherein one or more ofthe non-terminal carbon atoms of each said (C₁-C₈)alkyl is optionallyreplaced with —O—, —S— or —NR^(a)—.
 2. The compound according to claim 1represented by Formula II

wherein X² is C—R¹⁰ and each Y and Y¹ is O.
 3. The compound according toclaim 2 wherein R⁸ is halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², OR¹¹ orSR¹¹.
 4. The compound according to claim 3 wherein R⁹ is H or NR¹¹R¹².5. The compound according to claim 4 wherein R⁷ is H or


6. The compound according to claim 1 wherein R⁵ is N₃.
 7. The compoundaccording to claim 6 wherein X² is C—H and R³ and R⁵ are each H.
 8. Thecompound according to claim 7 wherein at least one of R² or R⁴ isOR^(a).
 9. The compound according to claim 8 wherein X¹ is N or C—R¹⁰wherein R¹⁰ is H, halogen, CN or optionally substituted heteroaryl. 10.The compound according claim 9 wherein R² and R⁴ are each OR^(a). 11.The compound according to claim 10 wherein R² and R⁴ are OH.
 12. Thecompound according to claim 9 wherein R¹ is H, methyl, CH₂OH, CH₂F,ethenyl, or ethynyl.
 13. The compound according to claim 9 wherein X¹ isN.
 14. The compound according to claim 9 wherein X¹ is C—H.
 15. Thecompound according to claim 14 wherein

is selected from

wherein Y² is, independently, a bond, O, or CR₂.
 16. The compoundaccording to claim 9 wherein W¹ and W² are each, independently, a groupof the Formula Ia.
 17. The compound according to claim 9 wherein R⁷ isH.
 18. A compound that is

or a pharmaceutically acceptable salt thereof.
 19. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable carrier.
 20. Thepharmaceutical composition of claim 19 further comprising at least oneadditional therapeutic agent selected from the group consisting ofinterferons, ribavirin analogs, NS3 protease inhibitors, NS5ainhibitors, NS5b polymerase inhibitors, alpha-glucosidase 1 inhibitors,cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors ofHCV, and other drugs for treating HCV.
 21. A method of inhibiting HCVpolymerase comprising administering to a mammal in need thereof atherapeutically effective amount of a compound of claim
 1. 22. A methodof treating a viral infection caused by a virus selected from the groupconsisting of dengue virus, yellow fever virus, West Nile virus,Japanese encephalitis virus, tick-borne encephalitis virus, Kunjinvirus, Murray Valley encephalitis virus, St. Louis encephalitis virus,Omsk hemorrhagic fever virus, bovine viral diarrhea virus, Zika virusand Hepatitis C virus comprising administering to a mammal in needthereof a therapeutically effective amount of a compound orpharmaceutical composition of claim
 1. 23. The method of claim 22wherein the viral infection is caused by Hepatitis C virus.
 24. Themethod of claim 23 further comprising administering at least oneadditional therapeutic agent selected from the group consisting ofinterferons, ribavirin analogs, NS3 protease inhibitors, NS5b polymeraseinhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilininhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, andother drugs for treating HCV.